Polynucleotides encoding fatty acid transport proteins

ABSTRACT

A family of fatty acid transport proteins (FATPs) mediate transport of long chain fatty acids (LCFAs) across cell membranes into cells. These proteins exhibit different expression patterns among the organs of mammals. Nucleic acids encoding FATPs of this family, vectors comprising these nucleic acids, as well as the production of FATP proteins in host cells are described. Also described are methods to test FATPs for fatty acid transport function, and methods to identify inhibitors or enhancers of transport function. The altering of LCFA uptake by administering to the mammal an inhibitor or enhancer of FATP transport function of a FATP in the small intestine can decrease or increase calories available as fats, and can decrease or increase circulating fatty acids. The organ specificity of FATP distribution can be exploited in methods to direct drugs, diagnostic indicators and so forth to an organ such as the heart.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Number 60/071,374 entitled “Identification of a Family of Fatty Acid Transporters Conserved From Mycobacterium to Man,” by Andreas Stahl, David Hirsch and Harvey F. Lodish, filed on Jan. 15, 1998; U.S. Provisional Application Number 60/093,491 entitled “Fatty Acid Transport Proteins,” by Andreas Stahl, David J. Hirsch, Harvey F. Lodish, Ruth E. Gimeno and Louis A. Tartaglia, filed on Jul. 20, 1998; and U.S. Provisional Application Number 60/110,941 entitled “Fatty Acid Transport Proteins,” by Andreas Stahl, David J. Hirsch, Harvey F. Lodish, Ruth E. Gimeno and Louis A. Tartaglia, filed on Dec. 4, 1998. The teachings of each of these referenced applications are incorporated herein by reference in their entirety.

GOVERNMENT SUPPORT

The invention was supported, in whole or in part, by National Institutes of Health Grant DK 47618 and National Institutes of Health Grant 5 T32 CA 09541. The United States Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Long chain fatty acids (LCFAs) are an important source of energy for most organisms. They also function as blood hormones, regulating key metabolic functions such as hepatic glucose production. Although LCFAs can diffuse through the hydrophobic core of the plasma membrane into cells, this nonspecific transport cannot account for the high affinity and specific transport of LCFAs exhibited by cells such as cardiac muscle, hepatocytes, enterocytes, and adipocytes. The molecular mechanisms of LCFA transport remains largely unknown. Identifying these mechanisms can lead to pharmaceuticals that modulate fatty acid uptake by the intestine and by other organs, thereby alleviating certain medical conditions (e.g. obesity).

SUMMARY OF THE INVENTION

Described herein is a diverse family of fatty acid transport proteins (FATPs) which are evolutionarily conserved; these FATPs are plasma membrane proteins which mediate transport of LCFAs across the membranes and into cells. Members of the FATP family described herein are present in a wide variety of organisms, from mycobacteria to humans, and exhibit very different expression patterns in tissues among the organisms. FATP family members are expressed in prokaryotic and eukaryotic organisms and comprise characteristic amino acid domains or sequences which are highly conserved across family members. In addition, the function of the FATP gene family is conserved throughout evolution, as shown by the fact that the Caenorhabditis (C). elegans and mycobacterial FATPs described herein facilitate LCFA uptake when they are overexpressed in COS cells or Escherichia (E.) coli, respectively. FATPs are expressed in a wide variety of tissues, including all tissues which are important to fatty acid metabolism (uptake and processing).

In specific embodiments, FATPs of the present invention are from such diverse organisms as humans (Homo (H.) sapiens), mice, (Mus (M.) musculus), F. rubripes, C. elegans, Drosophila (D.) melanogaster, Saccharomyces (S.) cerevisiae, Aspergillus nidulans, Cochliobolu heterostrophus, Magnaporthe grisea and Mycobacterium (M.), such as M. tuberculosis. As described herein, four novel mouse FATPs, referred to as mmFATP2, mmFATP3, mmFATP4 and mmFATP5, and six human FATPs, referred to as hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5 and hsFATP6, have been identified. All four novel murine FATPs (mmFATP2-5) and a previously identified murine FATP (renamed herein FATP1) have orthologs in humans (hsFATP1-5); the sixth human FATP (hsFATP6) does not as yet have a mouse ortholog. The expression patterns of these FATPs vary, as described in detail below.

The present invention relates to FATP family members from prokaryotes and eukaryotes, nucleic acids (DNA, RNA) encoding FATPs, and nucleic acids which are useful as probes or primers (e.g., for use in hybridization methods, amplification methods) for example, in methods of detecting FATP-encoding genes, producing FATPs, and purifying or isolating FATP-encoding DNA or RNA. Also the subject of this invention are antibodies (polyclonal or monoclonal) which bind an FATP or FATPs; methods of identifying additional FATP family members (for example, orthologs of those FATPs described herein by amino acid sequence) and variant alleles of known FATP genes; methods of identifying compounds which bind to an FATP, or modulate or alter (enhance or inhibit) FATP function; compounds which modulate or alter FATP function; methods of modulating or altering (enhancing or inhibiting) FATP function and, thus, LCFA uptake into tissues of a mammal (e.g. human) by administering a compound or molecule (a drug or agent) which increases or reduces FATP activity; and methods of targeting compounds to tissues by administering a complex of the compound to be targeted to tissues and a component which is bound by an FATP present on cells of the tissues to which the compound is to be targeted. For example, a complex of a drug to be delivered to the liver and a component which is bound by an FATP present on liver cells (e.g., FATP5) can be administered.

In one embodiment, the present invention relates to modulating or altering (enhancing or inhibiting/reducing) LCFA uptake in the small intestine and, thus, increasing or reducing the number of calories in the form of fats available to an individual. In another embodiment, the present invention relates to inhibiting or reducing LCFA uptake in the small intestine in order to reduce circulating fatty acid levels; that is, LCFA uptake in the small intestine is reduced and, therefore, circulating (blood) levels are not as high as they otherwise would be. FATP4 has been shown to be expressed in epithelial cells of the small intestine and particularly in the brush border layer of the small intestine. FATP2 has also been shown to be expressed at low levels in epithelial cells of the small intestine, particularly in the duodenum. In contrast, FATP1, FATP3, FATP5 and FATP6 were not detected in any of the intestinal tissues. Thus, also described herein are FATPs which are present in the epithelial cell layer of the small intestine where they mediate LCFA uptake. These FATPs, particularly FATP4 and also FATP2, are targets for methods and drugs which block their function or activity and are useful in treating obesity, diabetes and heart disease. The ability of these FATPs to mediate fat uptake can be modulated or altered (enhanced or inhibited), thus modulating fat uptake in the small intestine. This can be done, for example, by administering to an individual, such as a human or other animal, a drug which blocks interaction of LCFAs with FATP4 and/or FATP2 in the small intestine, thus inhibiting LCFA passage into the cells of the small intestine. As a result, fat absorption is reduced and, although the individual has consumed a certain quantity of fat, the LCFAs are not absorbed to the same extent they would have been in the absence of the compound administered.

Thus, one embodiment of this invention is a method of reducing LCFA uptake (absorption) in the small intestine and, as a result, reducing caloric uptake in the form of fat. A further embodiment is a compound (drug) useful in inhibiting or reducing fat absorption in the small intestine. In another embodiment, the invention is a method of reducing circulating fatty acid levels by administering to an individual a compound which blocks interactions of LCFAs with FATP4 and/or FATP2 in the small intestine, thus inhibiting LCFA passage into cells of the small intestine. As a result, fatty acids pass into the circulatory system at a diminished level and/or rate, and circulating fatty acid levels are lower than they would be in the absence of the compound administered. This method is particularly useful for therapy in individuals who are at risk for or have hyperlipidemia. That is, it can be used to prevent the occurrence of elevated levels of lipids in the blood or to treat an individual in whom blood lipid levels are elevated. Also the subject of this invention is a method of identifying compounds which alter FATP function (and thus, in the case of FATP2 and/or FATP4, alter LCFA uptake in the small intestine).

In another embodiment, the present invention relates to a method of modulating or altering (enhancing or inhibiting) the function of FATP6, which is expressed at high levels in the heart. A method of inhibiting FATP6 function is useful, for example, in individuals with heart disease, such as ischemia, since reducing LCFA uptake into heart muscle in an individual who has ischemic heart disease, which may be manifested by, for example, angina or heart attack, can reduce symptoms or reduce the extent of damage caused by the ischemia. In this embodiment, a drug which inhibits FATP6 function is administered to an individual who has had or is having a heart attack, to reduce LCFA uptake by the individual's heart and, as a result, reduce the damage caused by ischemia. In a further embodiment, this invention is a method of targeting a compound, such as a therapeutic drug or an imaging reagent, to heart tissue by administering to an individual (e.g., a human) a complex of the compound and a component (e.g., a LCFA or LCFA-like compound) which is bound by an FATP (e.g., FATP6) present in cells of heart tissue.

In a further embodiment, LCFA uptake by the liver is modulated or altered (enhanced or reduced), in an individual. For example, a drug which inhibits the function of an FATP present in liver (e.g., FATP5) is administered to an individual who is diabetic, in order to reduce LCFA uptake by liver cells and, thus reduce insulin resistance.

The present invention, thus, provides methods which are useful to alter, particularly reduce, LCFA uptake in individuals and, as a result, to alter (particularly reduce), availability of the LCFAs for further metabolism. In a specific embodiment, the present invention provides methods useful to reduce LCFA uptake and, thus, fatty acid metabolism in individuals, with the result that caloric availability from fats is reduced, and circulating fatty acid levels are lower than they otherwise would be. These methods are useful, for example, as a means of weight control in individuals, (e.g., humans) and as a means of preventing elevated serum lipid levels or reducing serum lipid levels in humans. FATPs expressed in the small intestine, such as FATP4, are useful targets to be blocked in treating obesity (e.g., chronic obesity) or to be enhanced in treating conditions in which enhanced LCFA uptake is desired (e.g., malabsorption syndrome or other wasting conditions).

The identification of this evolutionarily conserved fatty acid transporter family will allow a better understanding of the mechanisms whereby LCFAs traverse the lipid bilayer as well as yield insight into the control of energy homeostasis and its dysregulation in diseases such as diabetes and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1S shows the amino acid sequence alignment of FATPs: mmFATP1 (SEQ ID NO:92), mmFATP2 (SEQ ID NO:93), mmFATP3 (SEQ ID NO:94), mmFATP4 (SEQ ID NO:95), mmFATP5 (SEQ ID NO:96), ceFATPa (SEQ ID NO:97), scFATP (SEQ ID NO:98) and mtFATP (SEQ ID NO:99). The underlining (amino acid residues 204-212 of mtFATP) indicates an AMP binding motif which is found in many classes of proteins; the underlining at amino acid residues 204-507 of the mtFATP sequence indicates the FATP 360 amino acid signature sequence.

FIGS. 2A-2D show results of LCFA uptake assays. FIGS. 2A-2D: COS cells were cotransfected using the DEAE-dextran method with the mammalian expression vectors pCDNA-CD2 either alone (control; FIG. 2A) or in combination with one of the FATP-containing expression vectors (pCDNA-mmFATP1, FIG. 2B; pCDNA-mmFATP2, FIG. 2C; or pCMV-SPORT2-mmFATP5, FIG. 2D) as described in Materials and Methods for Example 2. COS cells were gated on forward scatter (FSC) and side scatter (SS), and the results shown represent >10,000 cells. Cells exhibiting >300 CD2 fluorescence units (vertical line) representing 15% of all cells were deemed CD2 positive.

FIG. 3 is a graph of fluorescence of cells expressing a FATP gene. As in FIGS. 2A-2D, COS cells were cotransfected with pCDNA-CD2 either alone (control) or in combination with one of the FATP-containing expression vectors (pCDNA-mmFATP1, pCDNA-mmFATP2, pCMV-SPORT2-mmFATP5, or pCDNA-ceFATPb). The mean BODIPY-FA fluorescence of the CD2-positive cells is plotted; results shown represent the average of three experiments, each consisting of greater than 50,000 COS cells. Note that a logarithmic scale is used on the ordinate.

FIG. 4 is a graph of the uptake of palmitate with time. The full-length coding region of mtFATP (squares) or a control protein (TFE3; circles) was subcloned into the inducible, prokaryotic expression vector pET (Novagen). Expression from the resulting plasmid was induced (solid symbols) in transformed E. coli cells with 1 mM isopropyl-β-D-thiogalactoside (IPTG) for 1 hour, or cells were left uninduced (open symbols). Data points were done in triplicate and counts were normalized to the number of bacteria as determined by OD₆₀₀.

FIG. 5 is a phylogenetic tree produced by aligning complete and partial sequences for FATP genes from human, rat, mouse, puffer fish, D. melanogaster, C. elegans, S. cerevisiae, and M. tuberculosis using ClustalX and using these data to produce a phylogenetic tree using TreeViewPPC. The bar indicates the number of substitutions per residue, i.e., 0.1 corresponds to a distance of 10 substitutions per 100 residues.

FIG. 6 shows a comparison of the FATP signature sequences of mmFATP 1 (SEQ ID NO:1), mmFATP5, (SEQ ID NO:2), ceFATPa (SEQ ID NO:3), scFATP (SEQ ID NO:4) and mtFATP (SEQ ID NO:5).

FIG. 7 shows the sequence identity among the FATP family members and VLACs, based on the 360 amino acid signature sequence of FATP from FIG. 1.

FIGS. 8A and 8B are the mmFATP3 DNA sequence (SEQ ID NO:6).

FIG. 9 is the mmFATP3 protein sequence (SEQ ID NO:7).

FIGS. 10A and 10B are the mm FATP4 DNA sequence (SEQ ID NO:8).

FIG. 11 is the mmFATP4 protein sequence (SEQ ID NO:9).

FIGS. 12A and 12B are the mmFATP5 DNA sequence (SEQ ID NO:10).

FIG. 13 is the mmFATP5 protein sequence (SEQ ID NO:11).

FIGS. 14A and 14B are the hsFATP2 DNA sequence (SEQ ID NO:12).

FIG. 15 is the hsFATP2 protein sequence (SEQ ID NO:13).

FIGS. 16A and 16B are the hsFATP3 DNA sequence (SEQ ID NO:14).

FIG. 17 is the hsFATP3 protein sequence (SEQ ID NO:15).

FIGS. 18A and 18B are the hsFATP4 DNA sequence (SEQ ID NO:16).

FIG. 19 is the hsFATP4 protein sequence (SEQ ID NO:17).

FIGS. 20A and 20B are the hsFATP5 DNA sequence (SEQ ID NO:18).

FIG. 21 is the hsFATP5 protein sequence (SEQ ID NO:19).

FIGS. 22A and 22B are the hsFATP6 DNA sequence (SEQ ID NO:20).

FIG. 23 is the hsFATP6 protein sequence (SEQ ID NO:21).

FIGS. 24A and 24B are the mtFATP DNA sequence (SEQ ID NO:22).

FIG. 25 is the mtFATP protein sequence (SEQ ID NO:23).

FIGS. 26A-26E shows the DNA sequence (SEQ ID NO:24) and predicted amino acid sequence (SEQ ID NO:25) of human FATP1.

FIGS. 27A-27D shows the DNA sequence (SEQ ID NO:26) and predicted amino acid sequence (SEQ ID NO:27) of human FATP4.

FIG. 28A is a hydrophobicity plot for hsFATP1, showing that it has multiple membrane-spanning domains.

FIG. 28B is the amino acid composition of hsFATP1.

FIG. 28C is a hydrophilicity plot for hsFATP1, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIG. 29A is a hydrophobicity plot for hsFATP4, showing that it has multiple membrane-spanning domains.

FIG. 29B is a listing of the amino acid composition of hsFATP4.

FIG. 29C is a hydrophilicity plot for hsFATP4, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIGS. 30A-30F show a comparison of the nucleotide sequence of human FATP1 (SEQ ID NO:28) and the nucleotide sequence of mouse FATP1 (SEQ ID NO:29).

FIGS. 31A-31I show a comparison of the nucleotide sequence of human FATP4 (SEQ ID NO:30) and the nucleotide sequence of mouse FATP4 (SEQ ID NO:31).

FIGS. 32A-32C shows a comparison of the amino acid sequence of human FATP1 (SEQ ID NO:32) and the amino acid sequence of mouse FATP1 (SEQ ID NO:33). Shaded amino acid residues match the consensus sequence exactly

FIG. 33 shows a comparison at the amino acid level of human FATP4 (SEQ ID NO:34) and mouse FATP4 (SEQ ID NO:35). Shaded amino acid residues match the concensus sequence exactly.

FIGS. 34A-34D shows the nucleotide sequence (SEQ ID NO:36) and predicted amino acid sequence (SEQ ID NO:37) of hsFATP6.

FIG. 35A is a hydrophobicity plot for hsFATP6, showing that it has multiple membrane-spanning domains.

FIG. 35B is a listing of the amino acid composition of hsFATP6.

FIG. 35C is a hydrophilicity plot for hsFATP6, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIGS. 36A-36G shows an alignment of the amino acid sequences of hsFATP1 (SEQ ID NO:38), hsFATP4 (SEQ ID NO:39) and hsFATP6 (SEQ ID NO:40). Shaded amino acid residues match the consensus sequence exactly.

FIG. 37 shows results of assessment of fatty acid uptake by human FATP 1 and human FATP4. The percent of CD2-positive cells exhibiting a BODIPY-fluorescence of more than 300 arbitrary units is plotted for the three different conditions tested.

FIG. 38 is a graph showing uptake of tritiated oleate, with time, by 293 cells transfected with either (diamonds) a plasmid for expression of human FATP4 or (squares) a control plasmid.

FIGS. 39A-39C are an illustration of the amino acid sequences of human FATP4 (SEQ ID NO:41) and mouse FATP4 (SEQ ID NO:42) compared to human FATP1 (SEQ ID NO:43). Shown by underlining are the FATP consensus sequence (236-556 of hsFATP1) and the AMP-binding motif (246-254 of hsFATP1). The human FATPs were cloned by screening libraries with sequences from ESTs (expressed sequence tags). Mouse FATP4 was cloned by PCR using degenerate primers.

FIG. 40 is a graph showing the uptake, with time, of tritiated oleate by mouse enterocytes in the presence of no oligonucleotide (squares), sense oligonucleotide (circles) or antisense oligonucleotide (diamonds).

FIG. 41 is a bar graph showing uptake of tritiated oleate, by mouse enterocytes in the presence of various concentrations of antisense (solid bars), mismatch (stippled bars) or sense (lined bars) oligonucleotides.

FIG. 42 is a bar graph showing uptake of tritiated oleate and uptake of ³⁵S-labeled methionine by mouse enterocytes to which were added no oligonucleotide, the antisense oligonucleotide, or the mismatch oligonucleotide.

FIGS. 43A-43B show the nucleotide sequence of the gene encoding mouse FATP4 (SEQ ID NO:44).

FIG. 43C shows the amino acid sequence of mouse FATP4 protein (SEQ ID NO:45).

FIGS. 44A-44D show the hsFATP1 DNA sequence (SEQ ID NO:46). Coding region: 175-2115 (1941 nt).

FIG. 45 is the hsFATP1 protein sequence (SEQ ID NO:47).

FIGS. 46A and 46B are the hsFATP2 DNA sequence (SEQ ID NO:48). Coding region: 223-2085 (1863 nt).

FIG. 47 is the hsFATP2 protein sequence (SEQ ID NO:49).

FIG. 48 is the partial DNA sequence of hsFATP3 (SEQ ID NO:50). Coding region: 1-993.

FIG. 49 is the partial protein sequence of hsFATP3 (SEQ ID NO:51).

FIGS. 50A, 50B, and 50C are the hsFATP4 DNA sequence (SEQ ID NO:52). Coding region: 208-2139 (1932 nt).

FIG. 51 is the hsFATP4 protein sequence (SEQ ID NO:53).

FIG. 52 is the hsFATP5 partial DNA sequence (SEQ ID NO:54). Coding region: 1-1062.

FIG. 53 is the hsFATP5 partial protein sequence (SEQ ID NO:55).

FIGS. 54A, 54B, and 54C are the hsFATP6 DNA sequence (SEQ ID NO:56). Coding region: 643-2502 (1860 nt).

FIG. 55 is the hsFATP6 protein sequence (SEQ ID NO:57).

FIGS. 56A, 56B, and 56C are the rnFATP1 DNA sequence (rn=Rattus norvegicus; (SEQ ID NO:58). Coding region: 75-2015 (1941 nt).

FIG. 57 is the rnFATP1 protein sequence (SEQ ID NO:59).

FIGS. 58A, 58B, and 58C are the rnFATP2 DNA sequence (SEQ ID NO:60). Coding region: 795-2657 (1863 nt).

FIG. 59 is the rnFATP2 protein sequence (SEQ ID NO:61).

FIGS. 60A and 60B are the rnFATP4 partial DNA sequence (SEQ ID NO:62). Coding region: 1-1218.

FIG. 61 is the rnFATP4 partial DNA sequence (SEQ ID NO:63).

FIGS. 62A, 62B, and 62C are the mmFATP1 DNA sequence (SEQ ID NO:64). Coding region: 1-1944.

FIG. 63 is the mmFATP1 protein sequence (SEQ ID NO:65).

FIGS. 64A and 64B are the mmFATP2 DNA sequence (SEQ ID NO:66). Coding region: 121-1992 (1872 nt).

FIG. 65 is the mmFATP2 protein sequence (SEQ ID NO:67).

FIGS. 66A and 66B are the mmFATP3 partial DNA sequence (SEQ ID NO:68). Coding region: 1-1830.

FIG. 67 is the mmFATP3 partial protein sequence (SEQ ID NO:69).

FIGS. 68A, 68B, and 68C are the mmFATP4 DNA sequence (SEQ ID NO:70). Coding region: 1-1932.

FIGS. 69 is the mmFATP4 protein sequence (SEQ ID NO:71).

FIGS. 70A and 70B are the mmFATP5 DNA sequence (SEQ ID NO:72). Coding region: 60-2129.

FIG. 71 is the mmFATP5 protein sequence (SEQ ID NO:73).

FIGS. 72A and 72B are the dmFATP partial DNA sequence (dm=Drosophila melanogaster; SEQ ID NO:74). Coding region: 1-1773.

FIGS. 73 is the dmFATP partial protein sequence (SEQ ID NO:75).

FIG. 74 is the drFATP partial DNA sequence (dr=Danio rerio, zebrafish; SEQ ID NO:76) Coding region: 1-173.

FIG. 75 is the drFATP partial protein sequence (SEQ ID NO:77).

FIG. 76A and 76B are the ceFATPa DNA sequence (SEQ ID NO:78). Coding region: 1-1953.

FIG. 77 is the ceFATPa protein sequence (SEQ ID NO:79).

FIGS. 78A and 78B are the ceFATPb DNA sequence (SEQ ID NO:80). Coding region: 1-1968.

FIG. 79 is the ceFATPb protein sequence (SEQ ID NO:81).

FIGS. 80A and 80B are the chFATP DNA sequence (SEQ ID NO:82; ch=Cochliobolu heterostrophus). Coding region: 1-1932.

FIG. 81 is the chFATP protein sequence (SEQ ID NO:83).

FIG. 82 is the anFATP partial protein sequence (an=Aspergillus nidulans; SEQ ID NO:84). Coding region: 1-597.

FIG. 83 is the anFATP partial protein sequence (SEQ ID NO:85).

FIG. 84 is the mgFATP partial DNA sequence (mg=Magnaporthe grisea, rice blast; SEQ ID NO:86). Coding region: 1-522.

FIG. 85 is the mgFATP partial protein sequence (SEQ ID NO:87).

FIGS. 86A and 86B are the scFATP DNA sequence (SEQ ID NO:88). Coding region: 1-1872.

FIG. 87 is the scFATP protein sequence (SEQ ID NO:89).

FIGS. 88A and 88B are the mtFATP DNA sequence (SEQ ID NO:90).

FIG. 89 is the mtFATP protein sequence (SEQ ID NO:91). Coding region: 1-1794.

FIG. 90 is a concensus sequence of the FATP signature sequence (SEQ ID NO: 100), based on 23 independent sequences aligned in ClustalX. The height of the bar at each amino acid residue position indicates the degree of conservation at that position. Gaps have been inserted to maintain the strength of the alignment.

FIG. 91 is a hydrophilicity plot for hsFATP2, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIG. 92 is a hydrophilicity plot for the hsFATP3 partial protein, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIG. 93 is a hydrophilicity plot for the hsFATP5 partial protein, made using the Kyte-Doolittle method, averaging hydrophilicity values for 18 amino acid residues at a time.

FIGS. 94A-94J are a representation of the DNA sequence (SEQ ID NO:101) of the 3 gene, and the amino acid sequence (SEQ ID NO:102) of the 3 protein.

DETAILED DESCRIPTION OF THE INVENTION

As described herein, FATPs are a large evolutionarily conserved family of proteins that mediate the transport of LCFAs into cells. The family includes proteins which are conserved from mycobacteria to humans and exhibit very different expression patterns in tissues. Specific embodiments described include FATPs from mice, humans, nematodes, fungi and mycobacteria which have been shown to be functional LCFA transporters. The term “fatty acid transport proteins” (“FATPs”) as used herein, refers to the proteins described herein as FATP1, FATP2, FATP3, FATP4, FATP5 and FATP6, which have been described in one or more species of mammals, as well as mtFATP, ceFATP, scFATP, anFATP, mgFATP, and chFATP, and other proteins sharing at least about 50% amino acid sequence similarity, preferably at least about 60% sequence similarity, more preferably at least about 70% sequence similarity, and still more preferably, at least about 80% sequence similarity, and most preferably, at least about 90% sequence similarity in the approximately 360 amino acid signature sequence. The approximately 360 amino acid FATP signature sequence is shown in FIG. 1. The concensus sequence of the signature sequence is shown in FIG. 90. The nomenclature used herein to refer to FATPs includes a species-specific prefix (e.g., mm, Mus musculus; hs or h, Homo sapiens or human; mt M. tuberculosis; dm. D. melanogaster; ce, C. elegans; sc, Saccharomyces cerevisiae) and a number such that mammalian homologues in different species share the same number. For example, six human and five mouse FATP genes which are expressed in a variety of tissues are described herein and are referred to, respectively, as hsFATP1-hsFATP6 and mmFATP1-mmFATP5; for example, hsFATP4 and mmFATP4 are the human and mouse orthologs.

Expression patterns of human and mouse FATPs have been assessed and are described below. Briefly, results of these assessments show that FATP5 is a liver-specific gene. FATP2 is highly expressed in liver and kidney. Both of these proteins, as well as FATP4 and FATPs from nematodes and mycobacteria, have been shown to be functional LCFA transporters. Results have also shown that FATP4 mRNA is present at high levels in epithelial cells of two regions of the small intestine (the jejunum and ileum) and at lower, but significant, levels in a third region (the duodenum). They further showed that FATP2 mRNA is present in epithelial cells of the duodenum at a level similar to that of FATP4 mRNA levels, but is present at lower levels in the jejunum and ileum. FATP4 mRNA was absent from other cell types of the small intestine and no FATP4 mRNA could be detected in any cells of the colon. No signals above background could be detected for FATP1, FATP3 and FATP5 in any of the intestinal tissues. Thus, FATP4 is the major FATP in the mouse small intestine, which supports a major role for FATP4 (along with FATP2 to a lesser extent) in absorption of free fatty acids. hsFATP4 was clearly expressed in the jejunum and ileum; expression was absent in the stomach. This, too, is consistent with a major role for FATP4 in absorption of fatty acids in the human gut. Analysis of FATP expression in human tissues, also described in detail below, showed that hsFATP6, which has no mouse ortholog as yet, is expressed at high levels in the heart and at low levels in the placenta, but is undetectable in the other tissues assessed (Example 9). This is consistent with a major role for FATP6 in absorption of fatty acids in the heart.

Long chain fatty acids (LCFAs) are an important energy source for pro- and eukaryotes and are involved in diverse cellular processes, such as membrane synthesis, intracellular signaling, protein modification, and transcriptional regulation. In developed Western countries, human dietary lipids are mainly di- and triglycerides and account for approximately 40% of caloric intake (Weisburger, J. H. (1997) J. Am. Diet. Assoc. 97:S16-S23). These lipids are broken down into fatty acids and glycerol by pancreatic lipases in the small intestine (Chapus, C., Rovery, M., Sarda, L & Verger, R. (1988) Biochimie 70:1223-34); LCFAs are then transported into brush border cells, where the majority is re-esterified and secreted into the lymphatic system as chylomicrons (Green, P. H. & Riley, J. W. (1981) Aust. N.Z.J. Med. 11:84-90). Fatty acids are liberated from lipoproteins by the enzyme lipoprotein lipase, which is bound to the luminal side of endothelial cells (Scow, R. O. & Blachette-Mackie, E. J. (1992) Mol. Cell. Biochem 116:181-191). “Free” fatty acids in the circulation are bound to serum albumin (Spector, A. A. (1984) Clin. Physiol. Biochem 2:123-134) and are rapidly incorporated by adipocytes, hepatocytes, and cardiac muscle cells. The latter derive 60-90% of their energy through the oxidation of LCFAs (Neely, J. F. Rovetto, M. J. & Oram, J. F. (1972) Prog. Cardiovasc. Dis: 15:289-329). Although saturable and specific uptake of LCFAs has been demonstrated for intestinal cells, hepatocytes, cardiac myocytes, and adipocytes, the molecular mechanisms of LCFA transport across the plasma membrane have remained controversial (Hui, T. Y. & Bernlohr, D. A. (1997) Front. Biosci. 15:d222-31-d231; Schaffer, J. E. & Lodish, H. F, (1995) Trends Cardiovasc. Med. 5:218-224). Described herein is a large family of highly homologous mammalian LCFA transporters which show wide expression, including in all tissues relevant to fatty acid metabolism. Further described are novel members of this family in other species, including mycobacterial and nematode FATPs which, like their mammalian counterparts, are functional fatty acid transporters.

The discovery of a diverse but highly homologous family of FATPs is reminiscent of the glucose transporter family. In a manner similar to the FATPs, the glucose transporters have very divergent patterns of tissue expression (McGowan, K. M., Long, S. D. & Pekala, P. H. (1995) Pharmacol. Ther. 66:465-505). The FATPs, like glucose transporters, may also differ in their substrate specificities, uptake kinetics, and hormonal regulation (Thorens, B. (1996) Am. J. Physiol. 270:G541-G553). Indeed, the levels of fatty acids in the blood, like those of glucose, can be regulated by insulin and are dysregulated in diseases such as noninsulin-dependent diabetes and obesity (Boden, G. (1997) Diabetes 46:3-10). The underlying mechanisms for the regulation of free fatty acid concentrations in the blood are not understood, but could be explained by hormonal modulation of FATPs.

Insulin-resistance is thought to be the major defect in non insulin-dependent diabetes mellitus (NIDDM) and is one of the earliest manifestations of NIDDM (McGarry (1992) Science 258:766-770). Free fatty acids (FFAs) may provide an explanation for why obesity is a risk factor for NIDDM. Plasma levels of FFAs are elevated in diabetic patients (Reaven et al. (1988) Diabetes 37:1020). Elevated plasma free fatty acids (FFAs) have been demonstrated to induce insulin-resistance in whole animals and humans (Boden (1998) Front. Biosci. 3:D169-D175). This insulin-resistance is likely mediated by effects of FFAs on a variety of issues. FFAs added to adipocytes in vitro induce insulin resistance in this cell type as evidenced by inhibition of insulin-induced glucose transport (Van Epps-Fung et al. (1997) Endocrinology 138:4338-4345). Rats fed a high fat diet developed skeletal muscle insulin resistance as evidenced by a decrease in insulin-induced glucose uptake by skeletal muscle (Han et al., (1997) Diabetes 46:1761-1767). In addition, elevated plasma FFAs increase insulin-suppressed endogenous glucose production in the liver (Boden (1998) Front. Biosci. 3:D169-D175), thus increasing hepatic glucose output. It has been postulated that the adverse effects of plasma free fatty acids are due to the FFAs being taken up into the cell, leading to an increase in intracellular long chain fatty acyl CoA; intracellular long chain acyl CoAs are thought to mediate the effects of FFAs inside the cell. Thus, fatty acid induced insulin-resistance may be prevented by blocking uptake of FFAs into select tissues, in particular liver (by blocking FATP2 and/or FATP5), adipocyte (by blocking FATP1), and skeletal muscle (by blocking FATP1). Blocking intestinal fat absorption (by blocking FATP4) is also expected to reduce plasma FFA levels and thus improve insulin resistance.

During the pathogenesis of NIDDM insulin-resistance can initially be counteracted by increasing insulin output by the pancreatic beta cell. Ultimately, this compensation fails, beta cell function decreases and overt diabetes results (McGarry (1992) Science 258: 766-770). Manipulating beta cell function is a second point where fatty acid transporter blockers may be beneficial for diabetes. While no FATP homolog has been identified so far that is expressed in the beta cell of the pancreas, the data described below suggest the existence of such a transporter and the sequence information included herein provides the means to identify such a transporter by degenerate PCR, using primers to regions conserved in all FATP family members or by low stringency hybridization. It has been demonstrated that exposure of pancreatic beta-cells to FFAs increases the basal rate of insulin secretion; this in turn leads to a decrease in the intracellular stores of insulin, resulting in decreased capacity for insulin secretion after chronic exposure (Bollheimer et al., (1998) J. Clin. Invest. 101:1094-1101). The effects of FFAs are again likely to be mediated by intracellular long chain fatty acyl CoA molecules (Liu et al., (1998) J. Clin. Invest. 101:1870-1875). FFAs have also been demonstrated to increase beta cell apoptosis (Shimabukuro et al., (1998) Proc. Nat. Acad. Sci. USA 95:2498-2502), possibly contributing to the decrease in beta cell numbers in late stage NIDDM.

Another finding with potentially broad implications is the identification of a FATP homologue in M. tuberculosis. Tuberculosis causes more deaths worldwide than any other infectious agent and drug-resistant tuberculosis is re-emerging as a problem in industrialized nations (Bloom, B. R. & Small, P. M. (1998) N. Engl. J. Med. 338:677-678). Mycobacterium tuberculosis has about 250 enzymes involved in fatty acid metabolism, compared with only about 50 in E. coli. It has been suggested that, living as a pathogen, the mycobacteria are largely lipolytic, rather than lipogenic, relying on the lipds within mammalian cells and the tubercle (Cole, S. T. et al., Nature 393:537-544 (1998)). The de novo synthesis of fatty acids in Mycobacterium leprae is insufficient to maintain growth (Wheeler, P. R., Bulmer, K & Ratledge, C. (1990) J. Gene. Microbiol. 136:211-217). Thus, it is reasonable to expect that inhibitors of mtFATP will serve as therapeutics for tuberculosis. FATPs expressed in mycobacteria can be targeted to reduce or prevent replication of mycobacteria (e.g., to reduce or prevent replication of M. tuberculosis) and, thus, reduce or prevent their adverse effects. For example, a FATP or FATPs expressed by M. tuberculosis can be targeted and inhibited, thus reducing or preventing growth of this pathogen (and tuberculosis in humans and other mammals). An inhibitor of an M. tuberculosis FATP can be identified, using methods described herein (e.g., expressing the FATP in an appropriate host cell, such as E. coli or COS cells; contacting the cells with an agent or drug to be assessed for its ability to inhibit the FATP and, as a result, mycobacterial growth, and assessing its effects on growth). A drug or agent identified in this manner can be further tested for its ability to inhibit a M. tuberculosis FATP and M. tuberculosis infection in an appropriate animal model or in humans. A method of inhibiting mycobacterial growth, particularly growth of M. tuberculosis, and compounds useful as drugs for doing so are also the subject of this invention.

An isolated polynucleotide encoding mtFATP, like other polynucleotides encoding FATPs of the FATP family, can be incorporated into vectors, nucleic acids of viruses, and other nucleic acid constructs that can be used in various types of host cells to produce mtFATP. This mtFATP can be used, as it appears on the surface of cells, or in various artificial membrane systems, to assess fatty acid transport function, to identify ligands and molecules that are modulators of fatty acid transport activity. Molecules found to be inhibitors of mtFATP function can be incorporated into pharmaceutical compositions to administer to a human for the treatment of tuberculosis.

Particular embodiments of the invention are polynucleotides encoding a FATP of Cochliobolus (Helminthosporium) heterostrophus or portions or variants thereof, the isolated or recombinantly produced FATP, methods for assessing whether an agent binds to the chFATP, and further methods for assessing the effect of an agent being tested for its ability to modulate fatty acid transport activity. Cochiobolus heterostrophus is an ascomycete that is the cause of southern corn leaf blight, an economically important threat to the corn crop in the United States. The related species C. sativus causes crown rot and common root rot in wheat and barley. One or more FATPs of C. heterostrophus can be targeted for the identification of an inhibitor of chFATP function, which can be then be used as an agent effective against infection of plants by C. heterostrophus and related organisms. Methods described herein that were applied in studying the expression of a FATP gene and the function of the FATP in its natural site of expression or in a host cell, can be used in the study of the chFATP gene and protein.

Magnaporthe grisea (rice blast) is an economically important fungal pathogen of rice. Further embodiments of the invention are nucleic acid molecules encoding a FATP of Magnaporthe grisea, portions thereof, or variants thereof, isolated mgFATP, nucleic acid constructs, and engineered cells expressing mgFATP. Other aspects of the invention are assays to identify an agent which binds to mgFATP and assays to identify an agent which modulates the function of mgFATP in cells in which mgFATP is expressed or in artificial membrane systems. Agents identified as inhibiting mgFATP activity can be developed into anti-fungal agents to be used to treat rice infected with rice blast.

Caenorhabditis elegans is a nematode related to plant pathogens and human parasites. An isolated polynucleotide which encodes ceFATP, like other polynucleotides encoding FATPs of the FATP family described herein, can be incorporated into nucleic acid vectors and other constructs that can be used in various types of cells to produce ceFATP. ceFATP as it occurs in cells or as it can be isolated or incorporated into various artificial or reconstructed membrane systems, can be used to assess fatty acid transport, and to identify ligands and agents that modulate fatty acid transport activity. Agents found by such assays to be inhibitors of ceFATP activity can be incorporated into compositions for the treatment of diseases caused by genetically related organisms with a FATP of similar sensitivity to the agents.

Aspergillus nidulans is one of a family of fungal species that can infect humans. Further embodiments of the invention of the family of polynucleotides encoding FATPs are polynucleotides encoding a FATP of Aspergillus nidulans, and vectors and host cells that can be constructed to comprise such polynucleotides. Further embodiments are a polypeptide encoded by such polynucleotides, portions thereof having one or more functions characteristic of a FATP, and various methods. The methods include those for identifying agents that bind to anFATP and those for assessing the effect of an agent being tested for its ability to modulate fatty acid transport activity. Those agents found to inhibit fatty acid transport function can be used in compositions as anti-fungal pharmaceuticals, or can be modified for greater effectiveness as a pharmaceutical.

One aspect of the invention relates to isolated nucleic acids that encode a FATP as described herein, such as those FATPs having an amino acid sequence in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A-94J (SEQ ID NO:102), and FIG. 55 (SEQ ID NO:57) and nucleic acids closely related thereto as described herein.

Using the information provided herein, such as a nucleic acid sequence set forth in FIGS. 44A-44D (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:38), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A-94J (SEQ ID NO:101), and FIGS. 54A-54C (SEQ ID NO:56), a nucleic acid of the invention encoding a FATP polypeptide may be obtained using standard cloning and screening methods, such as those for cloning and sequencing cDNA library fragments, followed by obtaining a full length clone. For example, to obtain a nucleic acid of the invention, a library of clones of cDNA of human or other mammalian DNA can be probed with a labeled oligonucleotide, such as radiolabeled oligonucleotide, preferably about 17 nucleotides or longer, derived from a partial sequence. Clones carrying DNA identical to that of the probe can then be distinguished using stringent (also, “high stringency”) hybridization conditions. By sequencing the individual clones thus identified with sequencing primers designed from the original sequence it is then possible to extend the sequence in both directions to determine the full length sequence. Suitable techniques are described, for example, in Current Protocols in Molecular Biology (F.M. Ausubel et al, eds), containing supplements through Supplement 42, 1998, Wiley and Sons, Inc., especially chapters 5, 6 and 7.

Embodiments of the invention include isolated nucleic acid molecules comprising any of the following nucleotide sequences: 1.) a nucleotide sequence which encodes a protein comprising the amino acid sequence of hsFATP1 (SEQ ID NO;47), the amino acid sequence of hsFATP2 (SEQ ID NO:49), the amino acid sequence of hsFATP3 (SEQ ID NO:102), the amino acid sequence of hsFATP4 (SEQ ID NO: 53), the amino acid sequence of hsFATP5 (SEQ ID NO: 55) or the amino acid sequence of hsFATP6 (SEQ ID NO:57); 2.) nucleotide sequences of hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5, or hsFATP6 (SEQ ID NO:46, 48, 101, 52, 54, or 56, respectively); 3.) a nucleotide sequence which is complementary to the nucleotide sequence of hsFATP1 (SEQ ID NO:46), hsFATP2 (SEQ ID NO:48), hsFATP3 (SEQ ID NO:101), hsFATP4 (SEQ ID NO:52), hsFATP5 (SEQ ID NO:54) or hsFATP6 (SEQ ID NO:56); 4.) a nucleotide sequence which consists of the coding region of hsFATP1 (SEQ ID NO:46), the coding region of hsFATP2 (SEQ ID NO:48), the coding region of hsFATP3 (SEQ ID NO:101), the coding region of hsFATP4 (SEQ ID NO:52), the coding region of hsFATP5 (SEQ ID NO:54), or the coding region of hsFATP6 (SEQ ID NO:56).

The invention further relates to nucleic acids (nucleic acid molecules or polynucleotides) having nucleotide sequences identical over their entire length to those shown in the figures, for instance FIGS. 44A-44D (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A-94J (SEQ ID NO:101), and FIGS. 54A-54C (SEQ ID NO:56). It further relates to DNA, which due to the degeneracy of the genetic code, encodes a FATP encoded by one of the FATP-encoding DNAs, whose amino acid sequence is provided herein. Also provided by the invention are nucleic acids having the coding sequences for the mature polypeptides or fragments in reading frame with other coding sequences, such as those encoding a leader or secretory sequence, a pre-, or pro- or prepro-protein sequence. The nucleic acids of the invention encompass nucleic acids that include a single continuous region or discontinuous regions encoding the polypeptide, together with additional regions, that may also contain coding or non-coding sequences. The nucleic acids may also contain non-coding sequences, including, for example, but not limited to, non-coding 5′ and 3′ sequences, such as the transcribed, non-translated sequences, termination signals, ribosome binding sites, sequences that stabilize mRNA, introns, polyadenylation signals, and additional coding sequences which encode additional amino acids. For example, a marker sequence that facilitates purification of the fused polypeptide can be encoded. In certain embodiments of the invention, the marker sequence can be a hexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) and described in Gentz et al., Proc. Natl. Acad. Sci. USA 86: 821-824 (1989), or an HA tag (Wilson et al., Cell 37: 767 (1984)), or a sequence encoding glutathione S-transferase of Schistosoma japonicum (vectors available from Phannacia; see Smith, D. B. and Johnson K. S., Gene 67:31 (1988) and Kaelin, W. G. et al., Cell 70:351 (1992)). Nucleic acids of the invention also include, but are not limited to, nucleic acids comprising a structural gene and its naturally associated sequences that control gene expression.

The invention further relates to variants, including naturally-occurring allelic variants, of those nucleic acids described specifically herein by DNA sequence, that encode variants of such polypeptides as those having the amino acid sequences shown in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A-94J (SEQ ID NO:102), or FIG. 55 (SEQ ID NO:57). Such variants include nucleic acids encoding variants of the above-listed amino acid sequences, wherein those variants have several, such as 5 to 10, 1 to 5, or 3, 2 or 1 amino acids substituted, deleted, or added, in any combination. Variants include polynucleotides encoding polypeptides with at least 95% but less than 100% amino acid sequence identity to the polypeptides described herein by amino acid sequence. Variant polynucleotides hybridize, under low to high stringency conditions, to the alleles described herein by DNA sequence. In one embodiment, variants have silent substitutions, additions and deletions that do not alter the properties and activities of the FATP. Allelic variants of the polynucleotides encoding hsFATP1 (FIG. 45; SEQ ID NO:47), hsFATP2 (FIG. 47; SEQ ID NO:49), hsFATP3 (FIG. 49; SEQ ID NO:51), hsFATP4 (FIG. 51; SEQ ID NO:53), hsFATP5 (FIGS. 94A-94J; SEQ ID NO:102) and hsFATP6 (FIG. 55; SEQ ID NO:57) will be identified as mapping to chromosomal locations listed for the corresponding wild type genes in Table 2 in Example 1.

Orthologous genes are gene loci in different species that are sufficiently similar to each other in their nucleotide sequences to suggest that they originated from a common ancestral gene. Orthologous genes arise when a lineage splits into two species, rather than when a gene is duplicated within a genome. Proteins that are orthologs are encoded by genes of two different species, wherein the genes are said to be orthologous.

The invention further relates to polynucleotides encoding polypeptides which are orthologous to those polypeptides having a specific amino acid sequence described herein, such as the amino acid sequences shown in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A-94J (SEQ ID NO:102), or FIG. 55 (SEQ ID NO:57). These polynucleotides, which can be called ortholog polynucleotides, encode orthologous polypeptides that can range in amino acid sequence identity to a reference amino acid sequence described herein, from about 65% to less than 100%, but preferably 70% to 80%, more preferably 80% to 90%, and still more preferably 90% to less than 100%. Orthologous polypeptides can also be those polypeptides that range in amino acid sequence similarity to a reference amino acid sequence described herein from about 75% to 100%, within the signature sequence. The amino acid sequence similarity between the signature sequences of orthologous polypeptides is preferably 80%, more preferably 90%, and still more preferably, 95%. The ortholog polynucleotides encode polypeptides that have similar functional characteristics (e.g., fatty acid transport activity) and similar tissue distribution, as appropriate to the organism from which the ortholog polynucleotides can be isolated.

Ortholog polynucleotides can be isolated from (e.g., by cloning or nucleic acid amplification methods) a great number of species, as shown by the sample of FATPs from evolutionarily divergent species described herein (see, e.g., FIGS. 44A-D through FIG. 89). Ortholog polynucleotides corresponding to those in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A-94J (SEQ ID NO: 102) and FIG. 55 (SEQ ID NO:57) are those which can be isolated from mammals such as rat, dog, chimpanzee, monkey, baboon, pig, rabbit and guinea pig, for example.

Further variants that are fragments of the nucleic acids of the invention may be used to synthesize full-length nucleic acids of the invention, such as by use as primers in a polymerase chain reaction. As used herein, the term primer refers to a single-stranded oligonucleotide which acts as a point of initiation of template-directed DNA synthesis under appropriate conditions (e.g., in the presence of four different nucleoside triphosphates and an agent for polymerization, such as DNA or RNA polymerase or reverse transcriptase) in an appropriate buffer and at a suitable temperature. The appropriate length of a primer depends on the intended use of the primer, but typically ranges from 15 to 30 nucleotides. Short primer molecules generally require cooler temperatures to form sufficiently stable hybrid complexes with the template. A primer need not reflect the exact sequence of the template, but must be sufficiently complementary to hybridize with a template. The term primer site refers to the area of the target DNA to which a primer hybridizes. The term primer pair refers to a set of primers including a 5′ (upstream) primer that hybridizes with the 5′ end of the DNA sequence to be amplified and a 3′ (downstream) primer that hybridizes with the complement of the 3′ end of the sequence to be amplified.

Further embodiments of the invention are nucleic acids that are at least 80% identical over their entire length to a nucleic acid described herein, for example a nucleic acid having the nucleotide sequence in FIGS. 44A-44D (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A-94J (SEQ ID NO:101), and FIGS. 54A-54C (SEQ ID NO:56). Additional embodiments are nucleic acids, and the complements of such nucleic acids, having at least 90% nucleotide sequence identity to the above-described sequences, and nucleic acids having at least 95% nucleotide sequence identity. In preferred embodiments, DNA of the present invention has 97% nucleotide sequence identity, 98% nucleotide sequence identity, or at least 99% nucleotide sequence identity with the DNA whose sequences are presented herein.

Other embodiments of the invention are nucleic acids that are at least 80% identical in nucleotide sequence to a nucleic acid encoding a polypeptide having an amino acid sequence as set forth in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A-94J (SEQ ID NO:102) or FIG. 55 (SEQ ID NO:57), or as such amino acid sequences are set forth elsewhere herein, and nucleic acids that are complementary to such nucleic acids. Specific embodiments are nucleic acids having at least 90% nucleotide sequence identity to a nucleic acid encoding a polypeptide having an amino acid sequence as described in the list above, nucleic acids having at least 95% sequence identity, and nucleic acids having at least 97% sequence identity.

The terms “complementary” or “complementarity” as used herein, refer to the natural binding of polynucleotides under permissive salt and temperature conditions by base-pairing. Complementarity between two single-stranded molecules may be “partial” in which only some of the nucleic acids bind, or it may be complete when total complementarity exists between the single-stranded molecules (that is, when A-T and G-C base pairing is 100% complete). The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. This is of particular importance in amplification reactions, which depend on binding between nucleic acid strands.

The invention further includes nucleic acids that hybridize to the above-described nucleic acids, especially those nucleic acids that hybridize under stringent hybridization conditions. “Stringent hybridization conditions” or “high stringency conditions” generally occur within a range from about T_(m) minus 5° C. (5° C. below the strand dissociation temperature or melting temperature (T_(m)) of the probe nucleic acid molecule) to about 20° C. to 25° C. below T_(m). As will be understood by those of skill in the art, the stringency of hybridization may be altered in order to identify or detect molecules having identical or related polynucleotide sequences. An example of high stringency hybridization follows. Hybridization solution is (6×SSC/10 mM EDTA/0.5% SDS/5×Denhardt's solution/100 μg/ml sheared and denatured salmon sperm DNA). Hybridization is at 64-65° C. for 16 hours. The hybridized blot is washed two times with 2×SSC/0.5% SDS solution at room temperature for 15 minutes each, and two times with 0.2×SSC/0.5% SDS at 65° C., for one hour each. Further examples of high stringency conditions can be found on pages 2.10.1-2.10.16 (see particularly 2.10.8-11) and pages 6.3.1-6 in Current Protocols in Molecular Biology (Ausubel, F. M. et al., eds., containing supplements up through Supplement 42, 1998). Examples of high, medium, and low stringency conditions can be found on pages 36 and 37 of WO 98/40404, which are incorporated herein by reference.

The invention further relates to nucleic acids obtainable by screening an appropriate library with a probe having a nucleotide sequence such as that set forth in FIGS. 44A-44D (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A-94J (SEQ ID NO:101) or FIGS. 54A-54C (SEQ ID NO:56), or a probe which is a sufficiently long fragment of any of the above; and isolating the nucleic acid. Such probes generally can comprise at least 15 nucleotides. Nucleic acids obtainable by such screenings may include RNAs, cDNAs and genomic DNA, for example, encoding FATPs of the FATP family described herein.

Further uses for the nucleic acid molecules of the invention, whether encoding a full-length FATP or whether comprising a contiguous portion of a nucleic acid molecule such as one given in SEQ ID NO:46, 48, 50, 52, 101, or 56, include use as markers for tissues in which the corresponding protein is preferentially expressed (to identify constitutively expressed proteins or proteins produced at a particular stage of tissue differentiation or stage of development of a disease state); as molecular weight markers on southern gels; as chromosome markers or tags (when labeled, for example with biotin, a radioactive label or a fluorescent label) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in a mammal to identify potential genetic disorders; as probes to hybridize and thus identify, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to “subtract-out” known sequences in the process of discovering other novel nucleic acid molecules; for selecting and making oligomers for attachment to a “gene chip” or other support, to be used, for example, for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or to elicit another immune response.

Further methods to obtain nucleic acids encoding FATPs of the FATP family include PCR and variations thereof (e.g., “RACE” PCR and semi-specific PCR methods). Portions of the nucleic acids having a nucleotide sequence set forth in FIGS. 44A-44D (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A-94J (SEQ ID NO:101) or FIGS. 54A-54C (SEQ ID NO:56), (especially “flanking sequences” on either side of a coding region) can be used as primers in methods using the polymerase chain reaction, to produce DNA from an appropriate template nucleic acid.

Once a fragment of the FATP gene is generated by PCR, it can be sequenced, and the sequence of the product can be compared to other DNA sequences, for example, by using the BLAST Network Service at the National Center for Biotechnology Information. The boundaries of the open reading frame can then be identified using semi-specific PCR or other suitable methods such as library screening. Once the 5′ initiator methionine codon and the 3′ stop codon have been identified, a PCR product encoding the full-length gene can be generated using genomic DNA as a template, with primers complementary to the extreme 5′ and 3′ ends of the gene or to their flanking sequences. The full-length genes can then be cloned into expression vectors for the production of functional proteins.

The invention also relates to isolated proteins or polypeptides such as those encoded by nucleic acids of the present invention. Isolated proteins can be purified from a natural source or can be made recombinantly. Proteins or polypeptides referred to herein as “isolated” are proteins or polypeptides that exist in a state different from the state in which they exist in cells in which they are normally expressed in an organism, and include proteins or polypeptides obtained by methods described herein, similar methods or other suitable methods, and also include essentially pure proteins or polypeptides, proteins or polypeptides produced by chemical synthesis or by combinations of biological and chemical methods, and recombinant proteins or polypeptides which are isolated. Thus, the term “isolated” as used herein, indicates that the polypeptide in question exists in a physical milieu distinct from that in which it occurs in nature. Thus, “isolated” includes existing in membrane fragments and vesicles membrane fractions, liposomes, lipid bilayers and other artificial membrane systems. An isolated FATP may be substantially isolated with respect to the complex cellular milieu in which it naturally occurs, and may even be purified essentially to homogeneity, for example as determined by PAGE or column chromatography (for example, HPLC), but may also have further cofactors or molecular stabilizers, such as detergents, added to the purified protein to enhance activity. In one embodiment, proteins or polypeptides are isolated to a state at least about 75% pure; more preferably at least about 85% pure, and still more preferably at least about 95% pure, as determined by Coomassie blue staining of proteins on SDS-polyacrylamide gels. Proteins or polypeptides referred to herein as “recombinant” are proteins or polypeptides produced by the expression of recombinant nucleic acids.

In a preferred embodiment, an isolated polypeptide comprising a FATP, a functional portion thereof, or a functional equivalent of the FATP, has at least one function characteristic of a FATP, for example, transport activity, binding function (e.g., a domain which binds to AMP), or antigenic function (e.g., binding of antibodies that also bind to a naturally-occurring FATP, as that function is found in an antigenic determinant). Functional equivalents can have activities that are quantitatively similar to, greater than, or less than, the reference protein. These proteins include, for example, naturally occurring FATPs that can be purified from tissues in which they are produced (including polymorphic or allelic variants), variants (e.g., mutants) of those proteins and/or portions thereof. Such variants include mutants differing by the addition, deletion or substitution of one or more amino acid residues, or modified polypeptides in which one or more residues are modified, and mutants comprising one or more modified residues. Portions or fragments of a FATP can range in size from four amino acid residues to the entire amino acid sequence minus one amino acid.

The isolated proteins of the invention preferably include mammalian fatty acid transport proteins of the FATP family of homologous proteins. In one embodiment, the extent of amino acid sequence similarity between a polypeptide having one of the amino acid sequences shown in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A94J (SEQ ID NO:102), or FIG. 55 (SEQ ID NO:57), and the respective functional equivalents of these polypeptides is at least about 88%. In other embodiments, the degree of amino acid sequence similarity between a FATP and its respective functional equivalent is at least about 91%, at least about 94%, or at least about 97%.

The polypeptides of the invention also include those FATPs encoded by polynucleotides which are orthologous to those polynucleotides, the sequences of which are described herein in whole or in part. FATPs which are orthologs to those described herein by amino acid sequence, in whole or in part, are, for example fatty acid transport proteins 1-6 of dog, rat chimpanzee, monkey, rabbit, guinea pig, baboon and pig, and are also embodiments of the invention.

To determine the percent identity or similarity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment, and non-homologous (dissimilar) sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 80%, or 90% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “similarity”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The invention also encompasses polypeptides having a lower degree of identity but having sufficient similarity so as to perform one or more of the same functions performed by the polypeptides described herein by amino acid sequence. Similarity for a polypeptide is determined by conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in a polypeptide by another amino acid of like characteristics. Conservative substitutions are likely to be phenotypically silent. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr, exchange of the acidic residues Asp and Glu, substitution between the amide residues Asn and Gln, exchange of the basic residues Lys and Arg and replacements among the aromatic residues Phe, Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent is found in Bowie et al, Science 247:1306-1310 (1990).

TABLE 1 Conservative Amino Acid Substitutions Aromatic Phenylalanine Tryptophan Tyrosine Hydrophobic Leucine Isoleucine Valine Polar Glutamine Asparagine Basic Arginine Lysine Histidine Acidic Aspartic Acid Glutamic Acid Small Alanine Serine Threonine Methionine Glycine

The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished using a mathematical algorithm. (Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing, Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereaux, J., eds., M. Stockton Press, New York, 1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al., Nucleic Acids Res. 12(1):387 (1984)) (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

The nucleic acid and protein sequences of the present invention can further be used as a “query sequence” to perform a search against databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, word length=12 to obtain nucleotide sequences homologous to (with calculatably significant similarity to) the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, word length=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (Nucleic Acids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

Similarity for nucleotide and amino acid sequences can be defined in terms of the parameters set by the Advanced Blast search available from NCBI (the National Center for Biotechnology Information; see, for Advanced BLAST page, www.ncbi.nlm.nih.gov/cgi-bin/BLAST/nph-newblast?Jform=1). These default parameters, recommended for a query molecule of length greater than 85 amino acid residues or nucleotides have been set as follows: gap existence cost, 11, per residue gap cost, 1; lambda ratio, 0.85. Further explanation of version 2.0 of BLAST can be found on related website pages and in Altschul, S. F. et al., Nucleic Acids Res. 25:3389-3402 (1997).

The invention further relates to fusion proteins, comprising a FATP or functional portion thereof (as described above) as a first moiety, linked to second moiety not occurring in the FATP as found in nature. Thus, the second moiety can be an amino acid, peptide or polypeptide. The first moiety can be in an N-terminal location, C-terminal location or internal to the fusion protein. In one embodiment, the fusion protein comprises a FATP as the first moiety, and a second moiety comprising a linker sequence and an affinity ligand. Fusion proteins can be produced by a variety of methods. For example, a fusion protein can be produced by the insertion of a FATP gene or portion thereof into a suitable expression vector, such as Bluescript SK +/− (Stratagene), pGEX-4T-2 (Pharmacia), pET-24(+) (Novagen), or vectors of similar construction. The resulting construct can be introduced into a suitable host cell for expression. Upon expression, fusion protein can be purified from cells by means of a suitable affinity matrix (See e.g., Current Protocols in Molecular Biology, Ausubel, F. M. et al., eds., Vol. 2, pp. 16.4.1-16.7.8, containing supplements up through Supplement 42, 1998).

The invention also relates to enzymatically produced, synthetically produced, or recombinantly produced portions of a fatty acid transport protein. Portions of a FATP can be made which have full or partial function on their own, or which when mixed together (though fully, partially, or nonfunctional alone), spontaneously assemble with one or more other polypeptides to reconstitute a functional protein having at least one function characteristic of a FATP.

Fragments of a FATP can be produced by direct peptide synthesis, for example those using solid-phase techniques (Roberge, J. Y. et al., Science 269:202-204 (1995); Merrifield, J., J. Am. Chem. Soc. 85:2149-2154 (1963)). Protein synthesis can be performed using manual techniques or by automation. Automated synthesis can be carried out using, for instance, an Applied Biosystems 431A Peptide Synthesizer (Perkin Elmer). Various fragments of a FATP can be synthesized separately and combined using chemical methods.

One aspect of the invention is a peptide or polypeptide having the amino acid sequence of a portion of a fatty acid transport protein which is hydrophilic rather than hydrophobic, and ordinarily can be detected as facing the outside of the cell membrane. Such a peptide or polypeptide can be thought of as being an extracellular domain of the FATP, or a mimetic of said extracellular domain. It is known, for example, that a portion of human FATP4 that includes a highly conserved motif is involved in AMP-CoA binding function (Stuhlsatz-Krouper, S. M. et al., J. Biol. Chem. 44:28642-28650 (1998)).

The term “mimetic” as used herein, refers to a molecule, the structure of which is developed from knowledge of the structure of the FATP of interest, or one or more portions thereof, and, as such, is able to effect some or all of the functions of a FATP.

Portions of an FATP can be prepared by enzymatic cleavage of the isolated protein, or can be made by chemical synthesis methods. Portions of a FATP can also be made by recombinant DNA methods in which restriction fragments, or fragments that may have undergone further enzymatic processing, or synthetically made DNAs are joined together to construct an altered FATP gene. The gene can be made such that it encodes one or more desired portions of a FATP. These portions of FATP can be entirely homologous to a known FATP, or can be altered in amino acid sequence relative to naturally occurring FATPs to enhance or introduce desired properties such as solubility, stability, or affinity to a ligand. A further feature of the gene can be a sequence encoding an N-terminal signal peptide directed to the plasma membrane.

An extracellular domain can be determined by a hydrophobicity plot, such as those shown in FIGS. 28A, 29A, and 35A, or by a hydrophilicity plot such as those shown in FIGS. 28C, 29C, 35C, 91, 92 and 93. A polypeptide or peptide comprising all or a portion of a FATP extracellular domain can be used in a pharmaceutical composition. When administered to a mammal by an appropriate route, the polypeptide or peptide can bind to fatty acids and compete with the native FATPs in the membrane of cells, thereby making fewer fatty acid molecules available as substrates for transport into cells, and reducing the amount of fatty acids taken up by, for example, the heart, in the case of FATP6.

Another aspect of the invention relates to a method of producing a fatty acid transport protein, variants or portions thereof, and to expression systems and host cells containing a vector appropriate for expression of a fatty acid transport protein.

Cells that express a FATP, a variant or a portion thereof, or an ortholog of a FATP described herein by amino acid sequence, can be made and maintained in culture, under conditions suitable for expression, to produce protein in the cells for cell-based assays, or to produce protein for isolation. These cells can be procaryotic or eucaryotic. Examples of procaryotic cells that can be used for expression include Escherichia coli, Bacillus subtilis and other bacteria. Examples of eucaryotic cells that can be used for expression include yeasts such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris and other lower eucaryotic cells, and cells of higher eucaryotes such as those from insects and mammals, such as primary cells and cell lines such as CHO, HeLa, 3T3 and BHK cells, preferably COS cells and human kidney 293 cells, and more preferably Jurkat cells. (See, e.g., Ausubel, F. M. et al, eds. Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, Inc., containing Supplements up through Supplement 42, 1998)).

In one embodiment, host cells that produce a recombinant FATP, or a portion thereof, a variant, or an ortholog of a FATP described herein by amino acid sequence, can be made as follows. A gene encoding a FATP, variant or a portion thereof can be inserted into a nucleic acid vector, e.g., a DNA vector, such as a plasmid, phage, cosmid, phagemid, virus, virus-derived vector (e.g., SV40, vaccinia, adenovirus, fowl pox virus, pseudorabies viruses, retroviruses) or other suitable replicon, which can be present in a single copy or multiple copies, or the gene can be integrated in a host cell chromosome. A suitable replicon or integrated gene can contain all or part of the coding sequence for a FATP or variant, operably linked to one or more expression control regions whereby the coding sequence is under the control of transcription signals and linked to appropriate translation signals to permit translation. The vector can be introduced into cells by a method appropriate to the type of host cells (e.g., transfection, electroporation, infection). For expression from the FATP gene, the host cells can be maintained tinder appropriate conditions (e.g., in the presence of inducer, normal growth conditions, etc.). Proteins or polypeptides thus produced can be recovered (e.g., from the cells, as in a membrane fraction, from the periplasmic space of bacteria, from culture medium) using suitable techniques. Appropriate membrane targeting signals may be incorporated into the expressed polypeptide. These signals may be endogenous to the polypeptide or they may be heterologous signals.

Polypeptides of the invention can be recovered and purified from cell cultures (or from their primary cell source) by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and high performance liquid chromatography. Known methods for refolding protein can be used to regenerate active conformation if the polypeptide is denatured during isolation or purification.

In a further aspect of the invention are methods for assessing the transport function of any of the fatty acid transport proteins or polypeptides described herein, including orthologs, and in variations of these, methods for identifying an inhibitor (or an enhancer) of such function and methods for assessing the transport function in the presence of a candidate inhibitor or a known inhibitor.

A variety of systems comprising living cells can be used for these methods. Cells to be used in fatty acid transport assays, and further in methods for identifying an inhibitor or enhancer of this function, express one or more FATPs. See Examples 3, 6, 9, 12 and 14 for data on tissue distribution of expression of FATPs, and Examples 10 and 11 describing recombinant cells expressing FATP. Cells for use in cell-based assays described herein can be drawn from a variety of sources, such as isolated primary cells of various organs and tissues wherein one or more FATPs are naturally expressed. In some cases, the cells can be from adult organs, and in some cases, from embryonic or fetal organs, such as heart, lung, liver, intestine, skeletal muscle, kidney and the like. Cells for this purpose can also include cells cultured as fragments of organs or in conditions simulating the cell type and/or tissue organization of organs, in which artificial materials may be used as substrates for cell growth. Other types of cells suitable for this purpose include cells of a cell strain or cell line (ordinarily comprising cells considered to be “transformed”) transfected to express one or more FATPs.

A further embodiment of the invention is a method for detecting, in a sample of cells, a fatty acid transport protein, a portion or fragment thereof, a fusion protein comprising a FATP or a portion thereof, or an ortholog as described herein, wherein the cells can be, for instance, cells of a tissue, primary culture cells, or cells of a cell line, including cells into which nucleic acid has been introduced. The method comprises adding to the sample an agent that specifically binds to the protein, and detecting the agent specifically bound to the protein. Appropriate washing steps can be added to reduce nonspecific binding to the agent. The agent can be, for example, an antibody, a ligand or a substrate mimic. The agent can have incorporated into it, or have bound to it, covalently or by high affinity non-covalent interactions, for instance, a label that facilitates detection of the agent to which it is bound, wherein the label can be, but is not limited to, a phosphorescent label, a fluorescent label, a biotin or avidin label, or a radioactive label. The means of detection of a fatty acid transport protein can vary, as appropriate to the agent and label used. For example, for an antibody that binds to the fatty acid transport protein, the means of detection may call for binding a second antibody, which has been conjugated to an enzyme, to the antibody which binds the fatty acid transport protein, and detecting the presence of the second antibody by means of the enzymatic activity of the conjugated enzyme.

Similar principles can also be applied to a cell lysate or a more purified preparation of proteins from cells that may comprise a fatty acid transport protein of interest, for example in the methods of immunoprecipitation, immunoblotting, immunoaffinity methods, that in addition to detection of the particular FATP, can also be used in purification steps, and qualitative and quantitative immunoassays. See, for instance, chapters 11 through 14 in Antibodies. A Laboratory Manual, E. Harlow and D. Lane, eds., Cold Spring Harbor Laboratory, 1988.

Isolated fatty acid transport protein or, an antigenically similar portion thereof, especially a portion that is soluble, can be used in a method to select and identify molecules which bind specifically to the FATP. Fusion proteins comprising all of, or a portion of, the fatty acid transport protein linked to a second moiety not occurring in the FATP as found in nature, can be prepared for use in another embodiment of the method. Suitable fusion proteins for this purpose include those in which the second moiety comprises an affinity ligand (e.g., an enzyme, antigen, epitope). FATP fusion proteins can be produced by the insertion of a gene encoding the FATP or a variant thereof, or a suitable portion of such gene into a suitable expression vector, which encodes an affinity ligand (e.g., pGEX-4T-2 and pET-15b, encoding glutathione S-transferase and His-Tag affinity ligands, respectively). The expression vector can be introduced into a suitable host cell for expression. Host cells are lysed and the lysate, containing fusion protein, can be bound to a suitable affinity matrix by contacting the lysate with an affinity matrix.

In one embodiment, the fusion protein can be immobilized on a suitable affinity matrix under conditions sufficient to bind the affinity ligand portion of the fusion protein to the matrix, and is contacted with one or more candidate binding agents (e.g., a mixture of peptides) to be tested, under conditions suitable for binding of the binding agents to the FATP portion of the bound fusion protein. Next, the affinity matrix with bound fusion protein can be washed with a suitable wash buffer to remove unbound candidate binding agents and non-specifically bound candidate binding agents. Those agents which remain bound can be released by contacting the affinity matrix with fusion protein bound thereto with a suitable elution buffer. Wash buffer can be formulated to permit binding of the fusion protein to the affinity matrix, without significantly disrupting binding of specifically bound binding agents. In this aspect, elution buffer can be formulated to permit retention of the fusion protein by the affinity matrix, but can be formulated to interfere with binding of the candidate binding agents to the target portion of the fusion protein. For example, a change in the ionic strength or pH of the elution buffer can lead to release of specifically bound agent, or the elution buffer can comprise a release component or components designed to disrupt binding of specifically bound agent to the target portion of the fusion protein.

Immobilization can be performed prior to, simultaneous with, or after, contacting the fusion protein with candidate binding agent, as appropriate. Various permutations of the method are possible, depending upon factors such as the candidate molecules tested, the affinity matrix-ligand pair selected, and elution buffer formulation. For example, after the wash step, fusion protein with binding agent molecules bound thereto can be eluted from the affinity matrix with a suitable elution buffer (a matrix elution buffer, such as glutathione for a GST fusion). Where the fusion protein comprises a cleavable linker, such as a thrombin cleavage site, cleavage from the affinity ligand can release a portion of the fusion with the candidate agent bound thereto. Bound agent molecules can then be released from the fusion protein or its cleavage product by an appropriate method, such as extraction.

One or more candidate binding agents can be tested simultaneously. Where a mixture of candidate binding agents is tested, those found to bind by the foregoing processes can be separated (as appropriate) and identified by suitable methods (e.g., PCR, sequencing, chromatography). Large libraries of candidate binding agents (e.g., peptides, RNA oligonucleotides) produced by combinatorial chemical synthesis or by other methods can be tested (see e.g., Ohlmeyer, M. H. J. et al., Proc. Natl. Acad. Sci. USA 90:10922-10926 (1993) and DeWitt, S. H. et al., Proc. Natl. Acad. Sci. USA 90:6909-6913 (1993), relating to tagged compounds; see also Rutter, W. J. et al. U.S. Pat. No. 5,010,175; Huebner, V. D. et al., U.S. Pat. No. 5,182,366; and Geysen, H. M., U.S. Pat. No. 4,833,092). Random sequence RNA libraries (see Ellington, A. D. et al., Nature 346:818-822 (1990); Bock, L. C. et al., Nature 355:584-566 (1992); and Szostak, J. W., Trends in Biochem. Sci. 17:89-93 (March, 1992)) can also be screened according to the present method to select RNA molecules which bind to a target FATP or FATP fusion protein. Where binding agents selected from a combinatorial library by the present method carry unique tags, identification of individual biomolecules by chromatographic methods is possible. Where binding agents do not carry tags, chromatographic separation, followed by mass spectrometry to ascertain structure, can be used to identify binding agents selected by the method, for example.

The invention also comprises a method for identifying an agent which inhibits interaction between a fatty acid transport protein (e.g., one comprising the amino acid sequence in SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:102, or SEQ ID NO:57), and a ligand of said protein. The FATP can be one described by amino acid sequence herein, a portion or fragment thereof, a variant thereof, or an ortholog thereof, or a FATP fusion protein. Here, a ligand can be, for instance, a substrate, or a substrate mimic, an antibody, or a compound, such as a peptide, that binds with specificity to a site on the protein. The method comprises combining, not limited to a particular order, the fatty acid protein, the ligand of the protein, and a candidate agent to be assessed for its ability to inhibit interaction between the protein and the ligand, under conditions appropriate for interaction between the protein and the ligand (e.g., pH, salt, temperature conditions conducive to appropriate conformation and molecular interactions); determining the extent to which the protein and ligand interact; and comparing (1) the extent of protein-ligand interaction in the presence of candidate agent with (2) the extent of protein-ligand interaction in the absence of candidate agent, wherein if (1) is less than (2), then the candidate agent is one which inhibits interaction between the protein and the ligand.

The method can be facilitated, for example, by using an experimental system which employs a solid support (column chromatography matrix, wall of a plate, microtiter wells, column pore glass, pins to be submerged in a solution, beads, etc.) to which the protein can be attached. Accordingly, in one embodiment, the protein can be fixed to a solid phase directly or indirectly, by a linker. The candidate agent to be tested is added under conditions conducive for interaction and binding to the protein. The ligand is added to the solid phase system under conditions appropriate for binding. Excess ligand is removed, as by a series of washes done under conditions that do not disrupt protein-ligand interactions. Detection of bound ligand can be facilitated by using a ligand that carries a label (e.g., fluorescent, chemiluminescent, radioactive). In a control experiment, protein and ligand are allowed to interact in the absence of any candidate agent, under conditions otherwise identical to those used for the “test” conditions where candidate inhibiting agent is present, and any washes used in the test conditions are also used in the control. The extent to which ligand binds to the protein in the presence of candidate agent is compared to the extent to which ligand binds to the protein in the absence of the candidate agent. If the extent to which interaction of the protein and the ligand occurs is less in the presence of the candidate agent than in the absence of the candidate agent, the candidate agent is an agent which inhibits interaction between the protein and the ligand of the protein.

In a further embodiment, an inhibitor (or an enhancer) of a fatty acid transport protein can be identified. The method comprises steps which are, or are variations of the following: contacting the cells with fatty acid, wherein the fatty acid can be labeled for convenience of detection; contacting a first aliquot of the cells with an agent being tested as an inhibitor (or enhancer) of fatty acid uptake while maintaining a second aliquot of cells under the same conditions but without contact with the agent; and measuring (e.g., quantitating) fatty acid in the first and second aliquots of cells; wherein a lesser quantity of fatty acid in the first aliquot compared to that in the second aliquot is indicative that the agent is an inhibitor of fatty acid uptake by a fatty acid transport protein. A greater quantity of fatty acid in the first aliquot compared to that in the second aliquot is indicative that the agent is an enhancer of fatty acid uptake by a fatty acid transport protein.

A particular embodiment of identifying an inhibitor or enhancer of fatty acid transport function employs the above steps, but also employs additional steps preceding those given above: introducing into cells of a cell strain or cell line (“host cells” for the intended introduction of, or after the introduction of, a vector) a vector comprising a fatty acid transport protein gene, wherein expression of the gene can be regulatable or constitutive, and providing conditions to the host cells under which expression of the gene can occur.

The terms “contacting” and “combining” as used herein in the context of bringing molecules into close proximity to each other, can be accomplished by conventional means. For example, when referring to molecules that are soluble, contacting is achieved by adding the molecules together in a solution. “Contacting” can also be adding an agent to a test system, such as a vessel containing cells in tissue culture.

The term “inhibitor” or “antagonist”, as used herein, refers to an agent which blocks, diminishes, inhibits, hinders, limits, decreases, reduces, restricts or interferes with fatty acid transport into the cytoplasm of a cell, or alternatively and additionally, prevents or impedes the cellular effects associated with fatty acid transport. The term “enhancer” or “agonist”, as used herein, refers to an agent which augments, enhances, or increases fatty acid transport into the cytoplasm of a cell. An antagonist will decrease fatty acid concentration, fatty acid metabolism and byproduct levels in the cell, leading to phenotypic and molecular changes.

In order to produce a “host cell” type suitable for fatty acid uptake assays and for assays derived therefrom for identifying inhibitors or enhancers thereof, a nucleic acid vector can be constructed to comprise a gene encoding a fatty acid transport protein, for example, human FATP1, FATP2, FATP3, FATP4, FATP5, FATP6, a mutant or variant thereof, an ortholog of the human proteins, such as mouse orthologs or orthologs found in other mammals, or a FATP family protein of origin in an organism other than a mammal. The gene of the vector can be regulatable, such as by the placement of the gene under the control of an inducible or repressible promoter in the vector (e.g., inducible or repressible by a change in growth conditions of the host cell harboring the vector, such as addition of inducer, binding or functional removal of repressor from the cell millieu, or change in temperature) such that expression of the FATP gene can be turned on or initiated by causing a change in growth conditions, thereby causing the protein encoded by the gene to be produced, in host cells comprising the vector, as a plasma membrane protein. Alternatively, the FATP gene can be constitutively expressed.

A vector comprising an FATP gene, such as a vector described herein, can be introduced into host cells by a means appropriate to the vector and to the host cell type. For example, commonly used methods such as electroporation, transfection, for instance, transfection using CaCl₂, and transduction (as for a virus or bacteriophage) can be used. Host cells can be, for example, mammalian cells such as primary culture cells or cells of cell lines such as COS cells, 293 cells or Jurkat cells. Host cells can also be, in some cases, cells derived from insects, cells of insect cell lines, bacterial cells, such as E. coli, or yeast cells, such as S. cerevisiae. It is preferred that the fatty acid transport protein whose function is to be assessed, with or without a candidate inhibitor or enhancer, be produced in host cells whose ancestor cells originated in a species related to the species of origin of the FATP gene encoding the fatty acid transport protein. For example, it is preferable that tests of function or of inhibition or enhancement of a mammalian FATP be carried out in host mammalian cells producing the FATP, rather than bacterial cells or yeast cells.

Host cells comprising a vector comprising a regulatable FATP gene can be treated so as to allow expression of the FATP gene and production of the encoded protein (e.g., by contacting the cells with an inducer compound that effects transcription from an inducible promoter operably linked to the FATP gene).

The test agent (e.g., an agonist or antagonist) is added to the cells to be used in a fatty acid transport assay, in the presence or absence of test agent, under conditions suitable for production and/or maintenance of the expressed FATP in a conformation appropriate for association of the FATP with test agent and substrate. For example, conditions under which an agent is assessed, such as media and temperature requirements, can, initially, be similar to those necessary for transport of typical fatty acid substrates across the plasma membrane. One of ordinary skill in the art will know how to vary experimental conditions depending upon the biochemical nature of the test agent. The test agent can be added to the cells in the presence of fatty acid, or in the absence of fatty acid substrate, with the fatty acid substrate being added following the addition of the test agent. The concentration at which the test agent can be evaluated can be varied, as appropriate, to test for an increased effect with increasing concentrations.

Test agents to be assessed for their effects on fatty acid transport can be any chemical (element, molecule, compound), made synthetically, made by recombinant techniques or isolated from a natural source. For example, test agents can be peptides, polypeptides, peptoids, sugars, hormones, or nucleic acid molecules, such as antisense nucleic acid molecules. In addition, test agents can be small molecules or molecules of greater complexity made by combinatorial chemistry, for example, and compiled into libraries. These libraries can comprise, for example, alcohols, alkyl halides, amines, amides, esters, aldehydes, ethers and other classes of organic compounds. Test agents can also be natural or genetically engineered products isolated from lysates of cells, bacterial, animal or plant, or can be the cell lysates themselves. Presentation of test compounds to the test system can be in either an isolated form or as mixtures of compounds, especially in initial screening steps.

Thus, the invention relates to a method for identifying agents which alter fatty acid transport, the method comprising providing the test agent to the cell (wherein “cell” includes the plural, and can include cells of a cell strain, cell line or culture of primary cells or organ culture, for example), under conditions suitable for binding to its target, whether to the FATP itself or to another target on or in the cell, wherein the transformed cell comprises a FATP.

In greater detail, to test one or more agents or compounds (e.g., a mixture of compounds can conveniently be screened initially) for inhibition of the transport function of a fatty acid transport protein, the agent(s) can be contacted with the cells. The cells can be contacted with a labeled fatty acid. The fatty acid can be, for example, a known substrate of the fatty acid transport protein such as oleate or palmitate. The fatty acid can itself be labeled with a radioactive isotope, (e.g., ³H or ¹⁴C) or can have a radioactively labeled adduct attached. In other variations, the fatty acid can have chemically attached to it a fluorescent label, or a substrate for an enzyme occurring within the cells, wherein the substrate yields a detectable product, such as a highly colored or fluorescent product. Addition of candidate inhibitors and labeled substrate to the cells comprising fatty acid transport protein can be in either order or can be simultaneous.

A second aliquot of cells, which can be called “control” cells (a “first” aliquot of cells can be called “test” cells), is treated, if necessary (as in the case of transformed “host” cells), so as to allow expression of the FATP gene, and is contacted with the labeled substrate of the fatty acid transport protein. The second aliquot of cells is not contacted with one or more agents to be tested for inhibition of the transport function of the protein produced in the cells, but is otherwise kept under the same culture conditions as the first aliquot of cells.

In a further step of a method to identify inhibitors of a fatty acid transport protein, the labeled fatty acid is measured in the first and second aliquots of cells. A preliminary step of this measurement process can be to separate the external medium from the cells so as to be able to distinguish the labeled fatty acid external to the cells from that which has been transported inside the cells. This can be accomplished, for instance, by removing the cells from their growth container, centrifuging the cell suspension, removing the supernatant and performing one or more wash steps to extensively dilute the remaining medium which may contain labeled fatty acid. Detection of the labeled fatty acid can be by a means appropriate to the label used. For example, for a radioactive label, detection can be by scintillation counting of appropriately prepared samples of cells (e.g., lysates or protein extracts); for a fluorescent label, by measuring fluorescence in the cells by appropriate instrumentation.

If a compound tested as a candidate inhibitor of transport function causes the test cells to have less labeled fatty acid detected in the cells than that detected in the control cells, then the compound is an inhibitor of the fatty acid transport protein. Procedures analogous to those above can be devised for identifying enhancers (agonists of FATPs) of fatty acid transport function wherein if the test cells contain more labeled fatty acid than that detected in the control cells, or if the fatty acid is taken up at a higher rate, then the compound being tested can be concluded to be an enhancer of the fatty acid transport protein.

Example 13 describes use of an assay of this type to identify an inhibitor of a FATP. In Example 13, an antisense oligonucleotide which specifically inhibits biosynthesis of mmFATP4 was demonstrated to inhibit fatty acid uptake into mouse enterocytes. Similarly, antisense oligonucleotides directed towards specifically inhibiting the biosynthesis of FATP6 in heart cells, FATP5 in liver cells, FATP3 in lung cells, and FATP2 in colon cells, can be demonstrated as examples of “test agents” that inhibit fatty acid transport.

Another assay to determine whether an agent is an inhibitor (or enhancer) of fatty acid transport employs animals, one or more of which are administered the agent, and one or more of which are maintained under similar conditions, but are not administered the agent. Both groups of animals are given fatty acids (e.g., orally, intravenously, by tube inserted into stomach or intestine), and the fatty acids taken up into a bodily fluid (e.g., serum) or into an organ or tissue of interest are measured from comparable samples taken from each group of animals. The fatty acids may carry a label (e.g., radioactive) to facilitate detection and quantitation of fatty acids taken up into the fluid or tissue being sampled. This type of assay can be used alone or can be used in addition to in vitro assays of a candidate inhibitor or enhancer.

An agent determined to be an inhibitor (or enhancer) of FATP function, such as fatty acid binding and/or fatty acid uptake, can be administered to cells in culture, or in vivo, to a mammal (e.g. human) to inhibit (or enhance) FATP function. Such an agent may be one that acts directly on the FATP (for example, by binding) or can act on an intermediate in a biosynthetic pathway to produce FATP, such as transcription of the FATP gene, processing of the mRNA, or translation of the mRNA. An example of such an agent is antisense oligonucleotide.

Antisense methods similar to those illustrated in Example 13 can be used to determine the target FATP of a compound or agent that has an inhibitory or enhancing effect on fatty acid uptake. For example, antisense oligonucleotide directed to the inhibition of FATP4 biosynthesis can be added to lung cells or cell lines derived from lung cells. In addition, antisense oligonucleotides directed to the inhibition of other FATPs, except for FATP3, can also be added to the lung cells. The administration of antisense oligonucleotides in this manner ensures that the predominant FATP activity remaining in the cells comes from FATP3. After a period of incubation of the cells with the antisense oligonucleotides sufficient to deplete the plasma membrane of the FATPs whose biosynthesis has been inhibited, a test agent, preferably one that has been shown by some preliminary test to have an inhibitory or enhancing activity on fatty acid transport, can be added to the lung cells. If the test agent is now demonstrated, after treatment of the cells with antisense oligonucleotides, to have an inhibitory or enhancing activity on fatty acid transport in the lung cells, it can be concluded that the target of the test agent is FATP3, or a molecule involved in the biosynthesis or activity of FATP3.

In another type of cell-based assay for uptake of fatty acids, a change of intracellular pH resulting from the uptake of fatty acids can be followed by an indicator fluorophore. The fluorophore can be taken up by the cells in a preincubation step. Fatty acids can be added to the cell medium, and after some period of incubation to allow FATP-mediated uptake of fatty acids, the change in λ_(max) of fluorescence can be measured, as an indicator of a change in intracellular pH, as the λ_(max) of fluorescence of the fluorophore changes with the pH of its environment, thereby indicating uptake of fatty acids. One such fluorophore is BCECF (2′, 7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein; Rink, T. J. et al., J. Cell. Biol. 95: 189 (1982)).

In assays similar to those described above, a candidate inhibitor or enhancer of fatty acid transport function can be added (or mock-added, for control cultures) to cultures of cells engineered to express a desired FATP to which fatty acid substrate is also added. Inhibition of fatty acid uptake is indicated by a lack of the drop in pH, indicating fatty acid uptake, that is seen in control cells. Enhancement of fatty acid uptake is indicated by a decrease in intracellular pH, as compared to control cells not receiving the candidate enhancer of fatty acid transport function.

Yeast cells can be used in a similar cell-based assay for the uptake of fatty acids mediated by a FATP, and such an assay can be adapted to a screening assay for the identification of agents that inhibit or enhance fatty acid uptake by an FATP. Yeast cells lacking an endogenous FATP activity (mutated, disrupted or deleted for FAT1; Faergeman, N. J. et al., J. Biol. Chem. 272(13):8531-8538 (1997); Watkins, P. A. et al., J. Biol. Chem. 273(29):18210-18219 (1998)) can be engineered to harbor a related gene of the family of FATP-encoding genes, such as a mammalian FATP (e.g., human FATP4).

Examples of expression vectors include pEG (Mitchell, D. A., et al., Yeast 9:715-723 (1993)) and pDAD1 and pDAD2, which contain a GAL1 promoter (Davis, L. I. and Fink, G. R., Cell 61:965-978 (1990)). A variety of promoters are suitable for expression. Available yeast vectors offer a choice of promoters. In one embodiment, the inducible GAL1 promoter is used. In another embodiment, the constitutive ADH1 promoter (alcohol dehyrodrogenase; Bennetzen, J. L. and Hall, B. D., J. Biol. Chem. 257:3026-3031 (1982)) can be used to express an inserted gene on glucose-containing media. An example of a vector suitable for expression of a heterologous FATP gene in yeast is pQB169.

With the introduced FATP gene providing the only fatty acid transport protein function for the yeast cells, it is possible to study effect of the heterologous FATP on fatty acid transport into the yeast cells in isolation. Assays for the uptake of fatty acids into the yeast cells can be devised that are similar to those described above and/or those assays that have been illustrated in the Examples. Tests for candidate inhibitors or enhancers of the heterologous FATP can be done in cultures of yeast cells, wherein the yeast cells are incubated with fatty acid substrate and an agent to be tested as an S inhibitor or enhancer of FATP function. FATP uptake after a period of time can be measured by analyzing the contents of the yeast cells for fatty acid substrate, as compared with control yeast cells incubated with the fatty acid, but not with the test agent. Yeast cells have the additional advantage, over mammalian cells in culture, for example, that yeast cells can be forced to rely upon fatty acids as their only source of carbon, if the growth medium supplied to the yeast cells is formulated to contain no other source of carbon. Thus, the effect of the heterologous FATP on fatty acid uptake and metabolism in the engineered yeast cells can be amplified. An agent that efficiently blocks transport function of the heterologous FATP could result in death of the yeast cells. Thus, in this case, inhibition of function of the heterologous FATP can result in loss of viability. A simple measure of viability is turbidity of the yeast suspension culture, which can be adapted to a high throughput screening assay for effects of various agents to be tested, using microtiter plates or similar devices for small-volume cultures of the engineered yeast cells.

Cell-free assays can also be used to measure the transport of fatty acids across a membrane, and therefor also to assess a test treatment or test agent for its effect on the rate or extent of fatty acid transport. An isolated FATP, for example in the presence of a detergent that preserves the native 3-dimensional structure of the FATP, or partially purified FATP, can be used in an artificial membrane system typically used to preserve the native conformation and activity of membrane proteins. Such systems include liposomes, artificial bilayers of phospholipids, isolated plasma membrane such as cell membrane fragments, cell membrane fractions, or cell membrane vesicles, and other systems in which the FATP can be properly oriented within the membrane to have transport activity. Assays for transport activity can be performed using methods analogous to those that can be used in cells engineered to predominantly express one FATP whose function is to be measured. A labeled (e.g., radioactively labeled) fatty acid substrate can be incubated with one side of a bilayer or in a suspension of liposomes constructed to integrate a properly oriented FATP. The accumulation of fatty acids with time can be measured, using appropriate means to detect the label (e.g., scintillation counting of medium on each side of the bilayer, or of the contents of liposomes isolated from the surrounding medium). Assays such as these can be adapted to use for the testing of agents which might interact with the FATP to produce an inhibitory or an enhancing effect on the rate or extent of fatty acid transport. That is, the above-described assay can be done in the presence or absence of the agent to be tested, and the results compared.

For examples of isolation of membrane proteins (ADP/ATP carrier and uncoupling protein), reconstitution into phospholipid vesicles, and assays of transport, see Klingenberg, M. et al., Methods Enzymol. 260:369-389 (1995). For an example of a membrane protein (phosphate carrier of Saccharomyces cerevisiae) that was purified and solubilized from E. coli inclusion bodies, see Schroer, A. et al., J. Biol. Chem. 273: 14269-14276 (1998). The Glut1 glucose transporter of rat has been expressed in yeast. A crude membrane fraction of the yeast was prepared and reconstituted with soybean phospholipids into liposomes. Glucose transport activity could be measured in the liposomes (Kasahara, T. and Kasahara, M., J. Biol. Chem. 273: 29113-29117 (1998)). Similar methods can be applied to the proteins and polypeptides of the invention.

Another embodiment of the invention is a method for inhibiting fatty acid uptake in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of an inhibitor of the transport function of one or more of the fatty acid transport proteins, thereby decreasing fatty acid uptake by cells comprising the fatty acid protein(s). Where it is desirable to reduce the uptake of fatty acids, for example, in the treatment of chronic obesity or as a part of a program of weight control or hyperlipidemia control in a human, one or more inhibitors of one or more of the fatty acid transport proteins can be administered in an effective dose, and by an effective route, for example, orally, or by an indwelling device that can deliver doses to the small intestine. The inhibitor can be one identified by methods described herein, or can be one that is, for instance, structurally related to an inhibitor identified by methods described herein (e.g., having chemical adducts to better stabilize or solubilize the inhibitor). The invention further relates to compositions comprising inhibitors of fatty acid uptake in a mammal, which may further comprise pharmaceutical carriers suitable for administration to a subject mammal, such as sterile solubilizing or emulsifying agents.

A further embodiment of the present invention is a method of enhancing or increasing fatty acid uptake, such as enhancing or increasing LCFA uptake in the small intestine (e.g., to treat or prevent a malabsorption syndrome or other wasting condition) or in the liver (e.g., by an enhancer of FATP5 transport activity to treat acute liver failure) or in the kidney (e.g., by an enhancer of FATP2 transport activity to treat kidney failure). In this embodiment, a therapeutically effective amount of an enhancer of the transport function of one or more of the fatty acid transport proteins can be administered to a mammalian subject, with the result that fatty acid uptake in the small intestine is enhanced. In this embodiment, one or more enhancers of one or more of fatty acid transport proteins is administered in an effective dose and by a route (e.g., orally or by a device, such as an indwelling catheter or other device) which can deliver doses to the gut. The enhancer of FATP function (e.g., an enhancer of FATP4 function) can be identified by methods described herein or can be one that is structurally similar to an enhancer identified by methods described herein.

Aerobic reperfusion of ischemic myocardium is a common clinical event which can occur during such treatments as cardiac surgery, angioplasty, and thrombolytic therapy after a myocardial infarction. During reperfusion, a rapid recovery of myocardial energy production is essential for the complete recovery of contractile function. Not only the extent of recovery of myocardial energy metabolism but also the type of energy substrate used by the heart during reperfusion are important determinants of functional recovery. Circulating fatty acid levels increase following acute myocardial infarction or during cardiac surgery, such that during and following ischemia the heart muscle can be exposed to very high concentrations of fatty acids (Lopaschuk, G. D. and W. C. Stanley, Science and Medicine (November/December 1997)). High plasma fatty acid concentrations increase the severity of ischemic damage in a number of experimental models of cardiac ischemia and have been linked to depression of mechanical function during aerobic reperfusion of previously ischemic hearts. Further data show that modifying fatty acid utilization can be beneficial for heart function in ischemia and can be a useful approach for the treatment of angina. See, e.g., Desideri and Celegon, Am. J. Cardiol. 82(5A):50K-53K; Lopaschuk, Am. J Cardiol. 82(5A): 14K-17K. Plasma fatty acid concentrations can be reduced by administering to a human subject or other mammal an effective amount of an inhibitor of a FATP such as FATP2 or FATP4, thereby providing a way of reducing fatty acid utilization by the heart.

In a further embodiment of the invention, a therapeutically effective amount of an inhibitor of hsFATP6 can be administered to a human patient by a suitable route, to reduce the uptake of fatty acids by cardiac muscle. This treatment is desirable in patients who are diagnosed as having, or who are at risk of, abnormal accumulations of fatty acids in the heart or a detrimentally high rate of uptake of fatty acids into the heart, because of ischemic heart disease, or following ischemia or trauma to the heart.

The invention further relates to antibodies that bind to an isolated or recombinant fatty acid transport protein of the FATP family, including portions of antibodies, which can specifically recognize and bind to one or more FATPs. The antibodies and portions thereof of the invention include those which bind to one or more FATPs of mouse or other mammalian species. In a preferred embodiment, the antibodies specifically bind to a naturally occurring FATP of humans. The antibodies can be used in methods to detect or to purify a protein of the present invention or a portion thereof by various methods of immunoaffinity chromatography, to inhibit the function of a protein in a method of therapy, or to selectively inactivate an active site, or to study other aspects of the structure of these proteins, for example.

The antibodies of the present invention can be polyclonal or monoclonal. The term antibody is intended to encompass both polyclonal and monoclonal antibodies. Antibodies of the present invention can be raised against an appropriate immunogen, including proteins or polypeptides of the present invention, such as an isolated or recombinant FATP1, FATP2, FATP3, FATP4, FATP5, FATP6, mtFATP, ceFATPa, ceFATPb, scFATP or portions thereof, or synthetic molecules, such as synthetic peptides (e.g., conjugated to a suitable carrier). Preferred embodiments are antibodies that bind to any of the following: hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5 or hsFATP6. The immunogen can be a polypeptide comprising a portion of a FATP and having at least one function of a fatty acid transport protein, as described herein.

The term antibody is also intended to encompass single chain antibodies, chimeric, humanized or primatized (CDR-grafted) antibodies and the like, as well as chimeric or CDR-grafted single chain antibodies, comprising portions from more than one species. For example, the chimeric antibodies can comprise portions of proteins derived from two different species, joined together chemically by conventional techniques or prepared as a single contiguous protein using genetic engineering techniques (e.g., DNA encoding the protein portions of the chimeric antibody can be expressed to produce a contiguous protein chain. See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., European Patent No. 0,125,023 B1; Boss et al., U.S. Pat. No. 4,816,397; Boss et al., European Patent No. 0,120,694 B1; Neuberger, M. S. et al., WO 86/01533; Neuberger, M. S. et al., European Patent No. 0,194,276 B1; Winter, U.S. Pat. No. 5,225,539; Winter, European Patent No. 0,239,400 B1; Queen et al., U.S. Pat. No. 5,585,089; and Queen et al., European Patent No. EP 0 451 216 B1. See also, Newman, R. et al., BioTechnology, 10:1455-1460 (1992), regarding primatized antibody, and Ladner et al., U.S. Pat. No. 4,946,778 and Bird, R. E. et al., Science, 242:423-426 (1988) regarding single chain antibodies.)

Whole antibodies and biologically functional fragments thereof are also encompassed by the term antibody. Biologically functional antibody fragments which can be used include those fragments sufficient for binding of the antibody fragment to a FATP to occur, such as Fv, Fab, Fab′ and F(ab′)₂ fragments. Such fragments can be produced by enzymatic cleavage or by recombinant techniques. For instance, papain or pepsin cleavage can generate Fab or F(ab′)₂ fragments, respectively. Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a chimeric gene encoding a F(ab′)₂ heavy chain portion can be designed to include DNA sequences encoding the CH₁ domain and hinge region of the heavy chain.

Preparation of immunizing antigen (whole cells comprising FATP on the cell surface or purified FATP), and polyclonal and monoclonal antibody production can be performed using any suitable technique. A variety of methods have been described (See e.g., Kohler et al., Nature, 256: 495-497 (1975) and Eur. J. Immunol. 6: 511-519 (1976); Milstein et al.; Nature 266: 550-552 (1977), Koprowski et al., U.S. Pat. No. 4,172,124; Harlow, E. and D. Lane, 1988, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory: Cold Spring Harbor, N.Y.); Chapter 11 In Current Protocols In Molecular Biology, Vol. 2 (containing supplements up through Supplement 42, 1998), Ausubel, F. M. et al., eds., (John Wiley & Sons: New York, N.Y.)). Generally, a hybridoma can be produced by fusing a suitable immortal cell line (e.g., a myeloma cell line such as SP2/0) with antibody producing cells. The antibody producing cells, preferably those obtained from the spleen or lymph nodes, can be obtained from animals immunized with the antigen of interest. Immunization of animals can be by introduction of whole cells comprising fatty acid transport protein on the cell surface. The fused cells (hybridomas) can be isolated using selective culture conditions, and cloned by limiting dilution. Cells which produce antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies (including human antibodies) of the requisite specificity can used, including, for example, methods which select recombinant antibody from a library (e.g., Hoogenboom et al., WO 93/06213; Hoogenboom et al., U.S. Pat. No. 5,565,332; WO 94/13804, published Jun. 23, 1994; and Dower, W. J. et al., U.S. Pat. No. 5,427,908), or which rely upon immunization of transgenic animals (e.g., mice) capable of producing a full repertoire of human antibodies (see e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90: 2551-2555 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Lonberg et al., U.S. Pat. No. 5,569,825; Lonberg et al., U.S. Pat. No. 5,545,806; Surani et al., U.S. Pat. No. 5,545,807; and Kucherlapati, R. et al., European Patent No. EP 0 463 151 B1).

Another aspect of the invention is a method for directing an agent to cardiac muscle. The differential expression of FATP6 in cardiac muscle but not in other tissue types allows for the specific targeting of drugs, diagnostic agents, tagging labels, histological stains or other substances specifically to cardiac muscle. A targeting vehicle can be used for the delivery of such a substance. Targeting vehicles which bind specifically to FATP6- can be linked to a substance to be delivered to the cells of cardiac muscle. The linkage can be, for instance, via one or more covalent bonds, or by high affinity non-covalent bonds. A targeting vehicle can be an antibody, for instance, or other compound (e.g., a fatty acid or fatty acid analog) which binds to FATP6 with high specificity.

Targeting vehicles specific to the heart-specific protein FATP6 have in vivo (e.g., therapeutic and diagnostic) applications. For example, an antibody which specifically binds to FATP6 can be conjugated to a drug to be targeted to the heart (e.g., a cardiac glycoside to treat congestive heart failure, or β-adrenergic agents, sodium channel blockers or calcium channel blockers to treat arrhythmias). A substance (e.g., a radioactive substance) which can be detected (e.g., a label) in vivo can also be linked to a targeting vehicle which specifically binds to a heart-specific protein such as FATP6, and the conjugate can be used as a labeling agent to identify cardiac muscle cells.

Targeting vehicles specific to FATP6 find further applications in vitro. For example, an FATP6-specific targeting vehicle, such as an antibody (a polyclonal preparation or monoclonal) which specifically binds to FATP6, can be linked to a substance which can be used as a stain for a tissue sample (e.g., horseradish peroxidase) to provide a method for the identification of cardiac muscle in a sample, as can be used in embryology studies, for example.

In a similar manner, an agent can be directed to the liver of a mammal, as FATP5 is expressed in liver but not in other tissue types. A targeting vehicle which specifically binds to FATP5 can be conjugated to a drug for delivery of the drug to the liver, such as a drug to treat hepatitis, Wilson's disease, lipid storage diseases and liver cancer. As with targeting vehicles specific to FATP6, targeting vehicles specific to FATP5 can be used in studying tissue samples in vitro.

The invention also relates to compositions comprising a modulator of FATP function. The term “modulate” as used herein refers to the ability of a molecule to alter the function of another molecule. Thus, modulate could mean, for example, inhibit, antagonize, agonize, upregulate, downregulate, induce, or suppress. A modulator has the capability of altering function of its target. Such alteration can be accomplished at any stage of the transcription, translation, expression or function of the protein, so that, for example, modulation of a target gene can be accomplished by modulation of the DNA or RNA encoding the protein, and the protein itself.

Antagonists or agonists (inhibitors or enhancers) of the FATPs of the invention, antibodies that bind a FATP, or mimetics of a FATP can be employed in combination with a non-sterile or sterile carrier or carriers for use with cells, tissues or organisms, such as a pharmaceutical carrier suitable for administration to a mammalian subject. Such compositions comprise, for instance, a media additive or a therapeutically effective amount of an inhibitor or enhancer compound to be identified by an assay of the invention and a pharmaceutically acceptable carrier or excipient. Such carriers may include, but are not limited to, saline, buffered saline, dextrose, water, ethanol, surfactants, such as glycerol, excipients such as lactose and combinations thereof. The formulation can be chosen by one of ordinary skill in the art to suit the mode of administration. The chosen route of administration will be influenced by the predominant tissue or organ location of the FATP whose function is to be inhibited or enhanced. For example, for affecting the function of FATP4, a preferred administration can be oral or through a tube inserted into the stomach (e.g., direct stomach tube or nasopharyngeal tube), or through other means to accomplish delivery to the small intestine. The invention further relates to diagnostic and pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention.

Compounds of the invention which are FATPs, FATP fusion proteins, FATP mimetics, FATP gene-specific antisense poly- or oligonucleotides, inhibitors or enhancers of a FATP may be employed alone or in conjunction with other compounds, such as therapeutic compounds. The pharmaceutical compositions may be administered in any effective, convenient manner, including administration by topical, oral, anal, vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, transdermal or intradermal routes, among others. In therapy or as a prophylactic, the active agent may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic.

Alternatively, the composition may be formulated for topical application, for example, in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.

In addition, the amount of the compound will vary depending on the size, age, body weight, general health, sex, and diet of the host, and the time of administration, the biological half-life of the compound, and the particular characteristics and symptoms of the disorder to be treated. Adjustment and manipulation of established dose ranges are well within the ability of those of skill in the art.

A further aspect of the invention is a method to identify a polymorphism, or the presence of an alternative or variant allele of a gene in the genome of an organism (of interest here, genes encoding FATPs). As used herein, polymorphism refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population. A polymorphic locus may be as small as a base pair. Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu. The first identified alleleic form, or the most frequently occurring form can be arbitrarily designated as the reference (usually, “wildtype”) form, and other allelic forms are designated as alternative (sometimes, “mutant” or “variant”). Dipolid organisms may be homozygous or heterozygous for allelic forms.

An “allele” or “allelic sequence” is an alternative form of a gene which may result from at least one mutation in the nucleotide sequence. Alleles may result in altered mRNAs or polypeptides whose structure or function may or may not be altered. Any given gene may have none, one, or many allelic forms (polymorphism). Common mutational changes which give rise to alleles are generally ascribed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.

Several different types of polymorphisms have been reported. A restriction fragment length polymorphism (RFLP) is a variation in DNA sequence that alters the length of a restriction fragment (Botstein et al., Am. J. Hum. Genet. 32:314-331 (1980)). The restriction fragment length polymorphism may create or delete a restriction site, thus changing the length of the restriction fragment. RFLPs have been widely used in human and animal genetic analyses (see WO 90/13668; WO 90/11369; Donis-Keller, Cell 51:319-337 (1987); Lander et al., Genetics 121:85-99 (1989)). When a heritable trait can be linked to a particular RFLP, the presence of the RFLP in an individual can be used to predict the likelihood that the individual will also exhibit the trait.

Other polymorphisms take the form of short tandem repeats (STRs) that include tandem di-, tri- and tetra-nucleotide repeated motifs. These tandem repeats are also referred to as variable number tandem repeat (VNTR) polymorphisms. VNTRs have been used in identity and paternity analysis (U.S. Pat. No. 5,075,217; Armour et al., FEBS Lett. 307:113-115 (1992); Horn et al., WO 91/14003; Jeffreys, EP 370,719), and in a large number of genetic mapping studies.

Other polymorphisms take the form of single nucleotide variations between individuals of the same species. Such polymorphisms are far more frequent than RFLPs, STRs (short tandem repeats) and VNTRs (variable number tandem repeats). Some single nucleotide polymorphisms occur in protein-coding sequences, in which case, one of the polymorphic forms may give rise to the expression of a defective or other variant protein and, potentially, a genetic disease. Other single nucleotide polymorphisms occur in noncoding regions. Some of these polymorphisms may also result in defective protein expression (e.g., as a result of defective splicing). Other single nucleotide polymorphisms have no phenotypic effects.

Many of the methods described below require amplification of DNA from target samples and purification of the amplified products. This can be accomplished by PCR, for instance. See generally, PCR Technology, Principles and Applications for DNA Amplification (ed. H. A. Erlich), Freeman Press, New York, N.Y., 1992; PCR Protocols: A Guide to Methods and Applications (eds. Innis, et al.), Academic Press, San Diego, Calif., 1990; Mattila et al., Nucleic Acids Res. 19:4967 (1991); Eckert et al., PCR Methods and Applications 1:17 (1991); PCR (eds. McPherson et al., IRS Press, Oxford); and U.S. Pat. No. 4,683,202.

Other suitable amplification methods include the ligase chain reaction (LCR) (see Wu and Wallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077 (1988)), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86:1173 (1989), self-sustained sequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87:1874 (1990), and nucleic acid based sequence amplification (NASBA). The latter two amplification methods involve isothermal reactions based on isothermal transcription, which produce both single stranded RNA (ssRNA) and double stranded DNA (dsDNA) as the amplification products in a ratio of about 30 or 100 to 1, respectively.

Another aspect of the invention is a method for detecting a variant allele of a human FATP gene, comprising preparing amplified, purified FATP DNA from a reference human and amplified, purified, FATP DNA from a “test” human to be compared to the reference as having a variant allele, using the same or comparable amplification procedures, and determining whether the reference DNA and test DNA differ in DNA sequence in the FATP gene, whether in a coding or a noncoding region, wherein, if the test DNA differs in sequence from the reference DNA, the test DNA comprises a variant allele of a human FATP gene. The following is a discussion of some of the methods by which it can be determined whether the reference FATP DNA and test FATP DNA differ in sequence.

Direct Sequencing. The direct analysis of the sequence of variant alleles of the present invention can be accomplished using either the dideoxy chain termination method or the Maxam and Gilbert method (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Press, New York 1989; Zyskind et al, Recombinant DNA Laboratory Manual, Acad. Press, 1988)).

Denaturing Gradient Gel Electrophoresis. Amplification products generated using the polymerase chain reaction can be analyzed by the use of denaturing gradient gel eletrophoresis. Different alleles can be identified based on the different sequence-dependent strand dissociation properties and electrophoretic migration of DNA in solution (chapter 7 in Erlich, ed. PCR Technology, Principles and Applications for DNA Amplification, W. H. Freeman and Co., New York, 1992).

Single-strand Conformation Polymorphism Analysis. Alleles of target sequences can be differentiated using single-strand conformation polymorphism analysis, which identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Natl. Acad. Sci. USA 86:2766-2770 (1989). Amplified PCR products can be generated as described above, and heated or otherwise denatured, to form single-stranded amplification products. Single-stranded nucleic acids may refold or form secondary structures which are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products can be related to base-sequence differences between alleles of target sequences.

Detection of Binding by Protein That Binds to Mismatches. Amplified DNA comprising the FATP gene or portion of the gene of interest from genomic DNA, for example, of a normal individual is prepared, using primers designed on the basis of the DNA sequences provided herein. Amplified DNA is also prepared, in a similar manner, from genomic DNA of an individual to be tested for bearing a distinguishable allele. The primers used in PCR carry different labels, for example, primer 1 with biotin, and primer 2 with ³²P. Unused primers are separated form the PCR products, and the products are quantitated. The heteroduplexes are used in a mismatch detection assay using immobilized mismatch binding protein (MutS) bound to nitrocellulose. The presence of biotin-labeled DNA wherein mismatched regions are bound to the nitrocellulose via MutS protein, is detected by visualizing the binding of streptavidin to biotin. See WO 95/12689. MutS protein has also been used in the detection of point mutations in a gel-mobility-shift assay (Lishanski, A. et al., Proc. Natl. Acad. Sci. USA 91:2674-2678 (1994)).

Other methods, such as those described below, can be used to distinguish a FATP allele from a reference allele, once a particular allele has been characterized as to DNA sequence.

Allele-specific probes. The design and use of allele-specific probes for analyzing polymorphims is described by e.g., Saiki et al, Nature 324:163-1 66 (1986); Dattagupta, EP 235,726, Saiki, WO 89/11548. Allele-specific probes can be designed so that they hybridize to a segment of a target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms in the respective segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles. Some probes are designed to hybridize to a segment of target DNA such that the polymorphic site aligns with a central position (e.g., in a 15-mer at the 7 position; in a 16-mer, at either the 8 or 9 position) of the probe. This design of probe achieves good discrimination in hybridization between different allelic forms.

Allele-specific probes are often used in pairs, one member of a pair showing a perfect match to a reference form of a target sequence and the other member showing a perfect match to a variant form. Several pairs of probes can then be immobilized on the same support for simultaneous analysis of multiple polymorphisms within the same target sequence.

Allele-specific Primers. An allele-specific primer hybridizes to a site on target DNA overlapping a polymorphism, and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. See Gibbs, Nucleic Acid Res. 17:2427-2448 (1989). This primer is used in conjunction with a second primer which hybridizes at a distal site. Amplification proceeds from the two primers, resulting in a detectable product which indicates the particular allelic form is present. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification and no detectable product is formed. The method works best when the mismatch is included in the 3′-most position of the oligonucleotide aligned with the polymorphism because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456).

Gene Chips. Allelic variants can also be identified by hybridization to nucleic acids immobilized on solid supports (gene chips), as described, for example, in WO 95/11995 and U.S. Pat. No. 5,143,854, both of which are incorporated herein by reference. WO 95/11995 describes subarrays that are optimized for detection of a characterized variant allele. Such a subarray contains probes designed to be complementary to a second reference sequence, which is an allelic variant of the first reference sequence.

The present method is illustrated by the following examples, which are not intended to be limiting in any way.

EXAMPLES Materials and Methods

The following Materials and Methods were used in the work described in Examples 1-5.

Sequence Alignment of FATP Clones. The DNA sequence for mouse FATP1 was obtained from the National Center for Biotechnology Information nonredundant database. cDNAs for mmFATP2, 3, 4, and 5 were obtained by screening mouse expression libraries (purchased from GIBCO/BRL) with probes derived from the cloned expressed sequence tags (ESTs) (Research Genetics, Huntsville, Ala.). Full-length clones were obtained for mmFATP2 and 5 and partial sequences for mmFATP3 and 4. The sequences described herein have been deposited in the GenBank database (Accession Nos. FATP2, AF072760; FATP3, AF072759; FATP4, AF072758; FATP5, AF072757).

Neither FATP2 nor FATP5 contains an in-frame stop codon upstream of the putative initiator methionine; initiator methionines were assigned by homology with that in mmFATP 1 and by the presence of a signal sequence immediately after it. The Mycobacterium tuberculosis, Caenorhabditis elegans, and Saccharomyces cerevisiae sequences were present in the dbEST database as part of the sequencing projects for these organisms. Sequences were aligned utilizing a ClustalX algorithm and the resulting alignment exported to SeqVu. Homologous amino acid substitutions are boxed in FIG. 1 and were determined using the Dayhoff 250 method with a 50% homology cutoff.

Cell Transfection and LCFA Uptake. COS cells were cotransfected using the DEAE-dextran method with the mammalian expression vector pCDNA 3.1 (Invitrogen) expressing the gene for CD2 (pCDNA-CD2) in combination with either a pCDNA 3.1 or pCMVSPORT2 (GIBCO/BRL) expression vector containing one of the murine or nematode FATP genes (pCDNA-mmFATP1 , pCDNA-FATP2, p CMVSPORT-FATP5, pCDNA-ceFATPb). Two days after transfection, cells were assayed for CD2 expression with a phycoerythrin-coupled anti-CD2(PE-CD2) monoclonal antibody (PharMingen), and fatty acid uptake was assayed with a BODIPY-labeled fatty acid analogue (Molecular Probes). Briefly, cells were washed twice with PBS (phosphate buffered saline) and stained with PE-CD2 at 4° C. for 30 min in PBS containing 10% fetal calf serum. They were then washed three times with PBS/fetal calf serum for 5 min followed by an incubation for 2 min at 37° C. in fatty acid uptake solution, which contained 0.1 μM BODIPY-FA and 0.1% fatty acid-free BSA (bovine serum albumin) in PBS (Schaffer, J. E. & Lodish, H. F. (1994) Cell 79:427-436). After 2 min, the cells were washed four times with ice-cold PBS/0.1% BSA. The cells were then removed from the plates with PBS containing 5 mM EDTA and resuspended in PBS containing 10% fetal calf serum and 10 mM EDTA. PE-CD2 and BODIPY-FA fluorescence were measured using a FACScan (Becton Dickinson). COS cells were gated on forward scatter (FSC) and side scatter (SS). Cells exhibiting more than 300 CD2 fluorescence units (dsim) representing 15% of all cells were deemed CD2 positive and their BODIPY-FA fluorescence was quantitated.

E. coli-Based LCFA Uptake Assay. The full-length coding region of mtFATP and a control protein, the mammalian transcription factor TFE3, were subcloned into the inducible, prokaryotic expression vector pET (Novagen). Expression was induced with 1 mM isopropyl β-D-thiogalactoside (IPTG) for 1 hour, or cells were left uninduced. Cells were washed in PBS/0.1% BSA and resuspended in 1 ml PBS/0.1% BSA containing 0.1 μM [³H]palmitate (NEN) at 37° C. . Uptake was stopped after the indicated incubation time by transferring the cells onto filter paper using a cell harvester (Brandel, Bethesda, Md.). Filters were washed extensively with ice-cold PBS/0.1% BSA, and [³H]palmitate was quantitated by scintillation counting.

Northern Blots. Northern blot analysis of murine FATP expression was done using poly(A) mRNA blots (Clontech). Probes of each of the FATPs were derived from the 3′ untranslated regions of each gene and were <60% identical in sequence. Probes were labeled by random priming (Boehringer Mannheim) and hybridized at 65 ° C. Blots were extensively washed in 0.2% SSC/0.1% SDS at 65° C.

Generation of Phylogenetic Trees. Complete and partial sequences for FATP genes from human, rat, mouse, puffer fish, Drosophila melanogaster, C. elegans, S. cerevisiae, and M. tuberculosis were aligned using ClustalX. A homologous region of 48 amino acids (residues 472-519 in mmFATP1) from all of the genes was used to determine phylogenetic relationship within ClustalX. Based on these data a phylogenetic tree was generated using Tree View PPC (FIG. 5).

Nomenclature. It is proposed that the FATP genes be given a species specific prefix (mm, Mus musculus; hs, Homo sapiens; mt, M. tuberculosis; dm, D. melanogaster; ce, C. elegans, sc, S. cerevisiae) and numbered such that mammalian homologues in different species share the same number but differ in their prefix. Since the two C. elegans genes cannot be paired with a specific human or mouse FATP, they have been designated ceFATPa and ceFATPb.

Example 1: Identification of Novel Mammalian FATPs

The National Center for Biotechnology Information EST database was screened, using the mouse FATP protein sequence (mmFATP 1), to identify novel FATPs. This strategy led to the identification of more than 50 murine EST sequences which could be assembled into five distinct contiguous DNA sequences (contigs). One contig was identical to the previously cloned FATP, which has been renamed FATP1. Another, which has been renamed FATP2, is the murine homologue of a rat gene previously identified by others as a very long chain acyl-CoA synthase (Uchiyama, A., Aoyama, T., Kamijo, K., Uchida, Y., Kondo, N., Orii, T. & Hashimoto, T. (1996) J. Biol. Chem. 271:30360-30365). The other three contigs represented novel genes (FATP3, 4, and 5). Full-length clones for FATP2 and FATP5 and nearly complete sequences for FATP3 and 4 (FIG. 1) were obtained by screening cDNA libraries made from mouse day 10.5 embryos and adult liver. Also identified were human homologues for each of the murine genes in the EST database. A sixth human gene was also identified; whether this gene is also present in the mouse will require additional studies. Map positions are given in Tables 2 and 3.

The genetic loci for all of the human genes, with the exception of FATP5 which was already mapped as an unknown EST, were determined using the radiation hybrid panels. The map positions given below show the distance (in centiRays) from the closest framework marker. As a guideline, there are approximately 300 kb/cR.

TABLE 2 Mapping Data for Human Genes hsFATP1 Chromosome Chr19 places 13.35 cR from WI-6344 (lod > 3.0) hsFATP2 Chromosome Chr15 places 4.92 cR from D15S126 (lod > 3.0) hsFATP3 Chromosome Chr1 places 13.24 cR from WI-2862 (lod > 3.0) hsFATP4 Chromosome Chr9 places 7.80 cR from WI-9685 (lod > 3.0) hsFATP5 unknown EST previously mapped to near D19S418 hsFATP6 Chromosome Chr5 places 1.41 cR from WI-4907 (lod > 3.0)

The mouse map is an internal backcross panel consisting of 188 mouse backcross DNA's plus 4 controls (B6, Spretus, F1, Water). The backcross was constructed by crossing B6 by Spretus animals and then crossing those F1's back to B6. Mapping is accomplished by taking advantage of recombinational events during meiosis, and the use of PCR primers to detect the differences (by size or re-annealing events) at any given locus between the B6 and Spretus allele.

For the purposes of mapping, a novel set of primers (gene of interest) is used to amplify from all 188 DNA's and then typed as being a B6 (“B”) or a Spretus (“S”). This string of B's and S's is entered into the Map Manager program, which does a best fit calculation by comparing the string of 188 typings from the gene of interest to all loci already extant in the panel, for all 20 chromosomes. The gene of interest is then assigned to a particular area on a particular chromosome according to a number of parameters, including the minimalization of double cross-overs, and the highest LOD scores. Indicated in Table 3 are distances to the closest markers on either side of the FATP locus.

TABLE 3 Mapping Data for Mouse Genes mmFATP1 Chromosome 8 places 2.82 cM from D8Mit132 (lod 43.4) and 1.81 cM from D8Mit74 (lod 43.5) mmFATP2 Chromosome 2 places 1.29 cM from D2Mit258 (lod 47.9) and 1.75 cM from D2NDS3 (lod 44.9) mmFATP3 Chromosome 3 places 2.54 cM from D3Mit22 (lod 29.5) and 19.62 cM from D3Mit42 (lod 13.6) mmFATP4 Chromosome 2 places 13.78 cM from D2Mit1 (lod 22.9) and 3.85 cM from D2Mit65 (lod 41.9) mmFATP5 Chromosome 7 places 7.28 cM proximal of D7Mit21 (lod 28.3)

Example 2: Assessment of Function

The ability of the newly identified mouse genes to function as fatty acid transporters was assessed using a fluorescence-activated cell sorting-based assay. COS cells were transiently cotransfected with expression vectors encoding the cell surface protein CD2 and either FATP1, mmFATP2, or mmFATP5, respectively. Two days after transfection, COS cells were stained with an antibody to CD2 and then incubated with a BODIPY-labeled fatty acid [BODIPY-FA, (Schaffer, J. E. & Lodish, H. F. (1994) Cell 79.427-436)]. The cells were then washed extensively, lifted off the dish, and analyzed by fluorescence-activated cell sorting. As judged by the number of CD2-positive cells, the transfection efficiency was approximately 20-30%. Fatty acid uptake was quantitated in the transiently transfected COS cells by measuring the BODIPY-FA fluorescence of the CD2-positive cells. Expression of CD2 had no effect on fatty acid uptake as shown by the finding that COS cells expressing only the transfected CD2 cDNA (CD2-positive) had the same low level of BODIPY-FA uptake as did untransfected (CD2-negative) control cells (FIG. 2A, control). In COS cells cotransfected with CD2 and mmFATP1, mmFATP2, or mmFATP5, uptake of BODIPY-FA by the transfected (CD2-positive) cells was increased between 15- to 90-fold over control (CD2 cDNA only) cells (FIGS. 2A-2D).

Example 3: Expression Patterns of Murine FATPs

Expression patterns of members of the murine FATP gene family were characterized by Northern blot analysis; to avoid cross-hybridization, the probes used were from the 3′ untranslated region of these genes, which are less than 60% identical in sequence. The expression pattern of FATP1 agrees with that previously found (Schaffer, J. E. & Lodish, H. F. (1994) Cell 79:427-436). Here, expression was seen primarily in heart and kidney. FATP2 is expressed almost exclusively in liver and kidney, which corresponds to the reported tissue distribution of the rat homologue [very long chain acyl-CoA (VLACS)] as assessed by Western blotting (Uchiyama, A., Aoyama, T., Kamijo, K., Uchida, Y., Kondo, N., Orii, T. & Hashimoto, T. (1996) J. Biol. Chem. 271:30360-30365). FATP3 is present in lung, liver, and testis. FATP5 is expressed only in liver and cannot be detected in other tissues even when the blot is overexposed. The human homologue of FATP5 is also liver specific and is not expressed in a wide array of other tissues tested, including fetal liver.

Example 4: FATPs Are Evolutionarily Conserved

The EST database was searched, using sequences conserved among the five murine FATP genes, for FATP genes in other organisms. Two homologues were found in C. elegans and one in M. tuberculosis. One of the C. elegans genes was cloned from a cDNA library and expressed in COS cells, as described for the murine FATPs. Overexpression of the nematode FATP resulted in a 15-fold increase of BODIPY-FA uptake compared with control cells (FIG. 3). The mycobacterial FATP gene was isolated from a phage library and assessed for its ability to facilitate fatty acid uptake. E. coli transformed with a prokaryotic, isopropyl β-D-thiogalactoside-inducible expression vector containing the mycobacterial FATP gene demonstrated a significant increase in the rate of [³H]palmitate uptake after induction, compared with uninduced bacteria or E. coli transformed with a control protein (FIG. 4). Novel FATP genes were also identified in F. rubripes (puffer fish) and D. melanogaster.

Example 5: Phylogenetic Tree of FATPs

Faergeman et al. (Faergeman, N. J., DiRusso. C. C., Elberger, A., Knudsen, J. & Black, P. N. (1997) J. Biol. Chem. 272:8531-8538) identified three regions of very strong conservation between the scFATP and mmFATP1 genes. The sequences of the FATPS were compared over a 311-amino acid FATP “signature sequence” which includes these conserved regions corresponding to amino acids 246-557 in mmFATP1 (underlined in FIG. 1). When compared with the National Center for Biotechnology Information nonredundant database, only one region of the “FATP signature sequence” shows significant homology to other proteins. This small stretch of amino acids (underlined in FIG. 1) is an AMP-binding motif found in a multitude of other proteins, such as acyl-CoA synthase, several CoA lipases, and gramicidin S synthetase component II (Schaffer, J. E. & Lodish, H. F. (1994) Cell 79:427-436). The relevance of this motif to fatty acid transport is unclear. Other highly conserved regions among the FATPs, including long stretches of amino acids >90% identical from mycobacteria to humans, are not found in any other class of proteins. A 48-amino acid segment of the FATP signature sequence was used to construct a phylogenetic tree (FIG. 5). Each of the human and mouse genes form their own branch; hsFATP6, which as yet has no murine homologue, is most closely related to hsFATP3 and mmFATP3. As expected, rnVLACS is closer in sequence to mmFATP2 than to hsFATP2. The FATP genes of invertebrates i.e., C. elegans and D. melanogaster, are most closely related to each other. Surprisingly, the mycobacteral gene is more closely related to the human and mouse FATP5 genes than to the FATPs of any of the lower organisms. Whether this reflects coevolution of the mycobacterial and human genes awaits further study.

Materials and Methods

The following materials and methods were used in the work described in Examples 6-10.

Isolation of Full-length Human FATP 1 and 4

Full-length clones encoding human FATP1 and human FATP4 were identified by searching databases for sequences similar to murine FATP1-5 coding regions using the BlastX algorithm (Altschul et al., J. Mol. Biol. 215: 403-410, 1990).

A concatamer of nucleotide sequences comprising the coding sequences of mmFATP1 (Genbank Accession U15976), mmFATP2, mmFATP3 (SEQ ID NO:6), mmFATP4 (SEQ ID NO:8) and mmFATP5 (SEQ ID NO:10) was used to search the Millennium database using the BLASTX algorithm. Sequences with a score >150 were evaluated for whether they represented known FATP coding sequences.

Human clones with similarity to the 5′ end of murine FATP sequences were sequenced completely. Clones encoding full-length human FATP1 were obtained from a heart cDNA library constructed in the mammalian expression vector pMET7 (Tartaglia et al., Cell, 83: 1263-1271, 1995). Clones encoding full-length human FATP4 were obtained from a spleen cDNA library constructed in the mammalian expression vector pMET7.

Isolation of Full-length Human FATP6

Several clones encoding human FATP6 were identified by searching public databases as described above. Five clones were analyzed further by restriction digestion and DNA sequencing. One of these clones (Genbank Accession #AA412064) appeared to be full-length and its entire insert was sequenced.

DNA Sequence Analysis

Sequences were aligned with the DNAStar program using the Clustal method. Hydrophobicity plots were generated with DNA Strider using the Kyte Doolittle method.

In situ Hybridization

Tissues were collected from 8 week old C57/B16 mice. Tissues were fresh frozen, cut on a cryostat at 10 μm thickness and mounted on Superfrost Plus slides (VWR). Sections were air dried for 20 minutes and then incubated with ice cold 4% paraformaldehyde (PFA)/phosphate buffered saline (PBS) for 10 minutes. Slides were washed 2 times 5 minutes with PBS, incubated with 0.25% acetic anhydride/1 M triethanolamine for 10 minutes, washed with PBS for 5 minutes and dehydrated with 70%, 80%, 95% and 100% ethanol for 1 minute each. Sections were incubated with chloroform for 5 minutes. Hybridizations were performed with ³⁵S-radiolabeled (5×10⁷ cpm/ml) cRNA probes generated from the 3′ untranslated regions of mouse FATPs by PCR followed by in vitro transcription in the presence of 50% formamide, 10% dextran sulfate, 1×Denhardt's solution, 600 mM NaCl, 10 mM DTT, 0.25% SDS and 10 μg/ml tRNA for 18 hours at 55 ° C. After hybridization, slides were washed with 10 mM Tris-HCl pH 7.6, 500 mM NaCl, 1 mM EDTA (TNE) for 10 minutes, incubated in 40 μg/ml RNase A in TNE at 37° C. for 30 minutes, washed in TNE for 10 minutes, incubated once in 2×SSC at 60° C. for 1 hour, once in 0.2×SSC at 60° C. for 1 hour, once in 0.2×SSC at 65° C. for 1 hour and dehydrated with 50%, 70%, 80%, 90% and 100% ethanol. Localization of mRNA transcripts was detected by dipping slides in Kodak NBT-2 photoemulsion and exposing for 7 days at 4° C., followed by development with Kodak Dektol developer. Slides were counter stained with haematoxylon and eosin and photographed. Controls for the in situ hybridization experiments include the use of a sense probe which showed no signal above background in all cases.

Northern Blotting

Human mRNA blots were obtained from Invitrogen or Clontech. PCR fragments from the 3′ untranslated regions of human FATPs were used as probes. Blots were probed with ³²P-labeled DNA probes using the Rapid-Hyb buffer (Amersham) according to the manufacturer's instructions.

Cell transfection and LCFA uptake. COS cells were cotransfected, using lipofectamine (GIBCO BRL) according to the manufacturer's instructions, with the mammalian expression vector pCDNA3.1 (Invitrogen) expressing the gene for CD2 in combination with a pMET7 expression vector (Tartaglia et al., Cell, 83:1263-1271, 1995) containing hsFATP1 (pMET7-hsFATP1) or hsFATP4 (pMET7-hsFATP4) or pMET7 alone. Two days after transfection, cells were assayed for CD2 expression with a phycoerythrin-coupled anti-CD2 (PE-CD2) monoclonal antibody (PharMingen), and fatty acid uptake was assayed with a BODIPY-labeled fatty acid analog (Molecular Probes) as described above.

Example 6: Determination of Expression of mmFATPs

mmFATP4, and to lesser extent mmFATP2, are expressed at high levels in the brush border layer of the small intestine.

Cell transfection and LCFA uptake. COS cells were cotransfected, using lipofectamine (GIBCO BRL) according to the manufacturer's instructions, with the mammalian expression vector pCDNA3.1 (Invitrogen) expressing the gene for CD2 in combination with a pMET7 expression vector (Tartaglia et al., Cell, 83:1263-1271, 1995) containing hsFATP1 (pMET7-hsFATP1) or hsFATP4 (pMET7-hsFATP4) or pMET7 alone. Two days after transfection, cells were assayed for CD2 expression with a phycoerythrin-coupled anti-CD2 (PE-CD2) monoclonal antibody (PharMingen), and fatty acid uptake was assayed with a BODIPY-labeled fatty acid analog (Molecular Probes) as described above.

Absorption of dietary fat requires transport of free fatty acids across the apical membrane of epithelial cells in the small intestine. Previous studies suggested that this transport is protein-mediated; however, the transport protein had not yet been identified. In situ hybridization was performed on each of the three regions of the small intestine—duodenum, jejunum and ileum—as well as the colon, using probes from the 3′ untranslated regions of mmFATP1, mmFATP2, mmFATP3, mmFATP4 and mmFATP5, to determine whether any of the mouse FATPs are expressed in the small intestine. It was expected that a protein involved in fatty acid absorption would be expressed in the epithelial cells of the small intestine, but absent from the colon.

Expression of mmFATPs in the jejunum was identical to that in the ileum in all cases. High levels of mmFATP4 mRNA were present in the epithelial cells of the jejunum and ileum, and lower, but significant, amounts were detected in the epithelial cells of the duodenum. Significantly, FATP4 mRNA was absent from other cell types of the small intestine and no FATP4 mRNA could be detected in any of the cells of the colon. FATP2 mRNA was present in the epithelial cells of the duodenum at a level similar to that of FATP4, but was present at lower levels in the jejunum and ileum. No signals above background were detected for mmFATP1, mmFATP3 and mmFATP5 in any of the intestinal tissues. mmFATP3 and FATP5 were clearly detectable by in situ hybridization in adult liver and mmFATP1 could be detected in a variety of tissues on a whole embryo in situ, indicating that the FATP 1, 3, and 5 probes were working.

mmFATP4 expression is predominant in the small intestine compared to the other organs of the mouse embryo. In the small intestine, FATP4 expression is limited to differentiated enterocytes, while no signal is detected in the connective tissue or the undifferentiated epithelial cells in the crypts. Differentiated enterocytes are known to be the cells that mediate the uptake of fatty acids. FATP4 is specifically and strongly expressed in the epithelial cells of adult murine duodenum and ileum but not colon. Other FATPs, such as FATP5, are not expressed in the small intestine. Thus, FATP4 is the major FATP in the mouse small intestine. Given its high level of expression, it is likely that FATP4, and to a lesser extent FATP2, play an important role in the absorption of fatty acids.

mmFATP2, and mmFATP5 are Expressed in Hepatocytes

Northern analysis of mmFATP2, mmFATP3, mmFATP4 and mmFATP5 showed expression in the liver. To determine whether these proteins are present in hepatocytes or other cells types present in liver homogenates, in situ hybridizations were performed. mmFATP2, and mmFATP5 mRNA was clearly present in hepatocytes, and was not concentrated in other cell types such as endothelial cells or macrophages. No signal above background was detected for mmFATP1 in any of the cell types in the liver, consistent with the results of the Northern blotting.

Example 7: Isolation and Sequence Analysis of Full-length Human FATP1 and Full-length Human FATP4

To identify human cDNA clones encoding FATP family members, Millennium databases were searched for sequences similar to murine FATP1-5 coding regions. Two clones were analyzed in detail; inspection of the entire DNA sequence of these two clones showed that they encode the human orthologs of mmFATP 1 and mm FATP4, respectively. These two clones were designated hsFATP 1 and hsFATP4, and their DNA and predicted protein sequences are shown in FIGS. 44A-44D and 45, and 50A-50C and 51. hsFATP 1 is predicted to encode a 646 amino acid, 71 kD protein with multiple membrane-spanning domains (FIG. 28A). HsFATP4 is predicted to encode a 643 amino acid, 72 kD protein with multiple membrane spanning domains (See FIG. 29A). A comparison of the DNA sequences of mouse and human FATP1and mouse and human FATP4 (FIGS. 30A-30F and 31A-31I) shows that the mouse and human orthologs are 85% (FATP1) and 87% (FATP4) identical to each other within the coding sequences given in these figures. At the amino acid level, hsFATP1 and hsFATP4 are ˜90% identical to their respective mouse orthologs within the coding region shown in these figures (FIGS. 32A-32C and 33A-33C). The sequence identities between mouse and human FATP1 and FATP4 are considerably higher than the ones observed between different FATP family members within one species (˜40%-60%) and are present in the N-terminal part of the protein, a region that is poorly conserved between different FATP family members. This high degree of sequence conservation clearly demonstrates that the newly identified human FATPs are orthologs of mouse FATP1and FATP4 rather than novel FATP family members.

Table 4 is an identity/similarity matrix comparing the amino acid sequences of FATP1and 4 from human and mouse. This shows that the gene whose sequence is shown in FIG. 43A is indeed human FATP4, since it is 91% identical with the murine FATP4 but only 62% identical with the closest related human FATP, which is FATP1.

TABLE 4 Identity/Similarity Matrix hsFATP4 mmFATP4 hsFATP1 mmFATP1 hsFATP4 — 93.2 72.3 72.0 mmFATP4 91.0 — 71.2 71.1 hsFATP1 61.9 61.0 — 92.4 mmFATP1 60.7 59.6 89.5 —

Example 8: Isolation and Sequence Analysis of Full-length Human FATP6

A search of EST databases identified a set of overlapping human sequences that were similar to FATPs, but did not have a clear mouse ortholog. One of these EST clones was found to encode a full-length cDNA. The entire insert of this clone was sequenced and designated hsFATP6. The DNA and predicted protein sequences of hsFATP6 are shown in FIGS. 54A-54C and 55. HsFATP6 is predicted to encode a 619 amino acid, 70 kD protein with multiple membrane-spanning domains (FIG. 35A). A comparison of the amino acid sequences of hsFATP6 with other human FATPs shows about 37% identity to either hsFATP1 or hsFATP4 (FIGS. 36A-36G). This degree of sequence identity is similar to what is observed between different mouse FATPs. The phylogenetic analysis described above clearly demonstrates that hsFATP6 is a member of the FATP family, but not an ortholog of any of the mouse FATPs. Comparisons were done with “ALIGN” (E. Myers and W. Miller, “Optimal Alignments in Linear Space,” CABIOS 4:11-17 (1988) using standard settings.

Example 9: Tissue Distribution of Human FATPs

The tissue distribution of human FATPs was assessed by Northern blotting. Human FATP3 was expressed in a large variety of tissues. In contrast, human FATP5 was present at high levels in the liver, but was undetectable in all other tissues examined. Thus, both hsFATP3 and hsFATP5 recapitulate the expression pattern of their mouse orthologs (see above). HsFATP6 is a novel FATP with no mouse ortholog as yet. Northern blotting shows that hsFATP6 is expressed at high levels in the heart, but is undetectable in other tissues, including skeletal and smooth muscle. This tissue distribution suggests that human FATP6 performs an important role in energy metabolism in the heart; blocking FATP6-mediated fatty acid transport may therefore be beneficial for a number of heart diseases, e.g., ischemic heart disease.

To identify the major FATP expressed in the human small intestine, Northern blotting was performed on a blot containing mRNA from human stomach, jejunum, ileum, colon, rectum and lung. hsFATP5 and hsFATP6 were undetectable in any of these tissues. FATP5 is only expressed in liver and FATP6 only in heart. hsFATP2 was weakly expressed in the colon, and an even weaker signal was detectable in jejunum, ileum and lung lanes. hsFATP3 was expressed well in the lung, but was only weakly expressed in the other tissues tested. Importantly, no difference was seen in the expression of hsFATP3 between small intestine and stomach or colon, suggesting that the expression observed is not related to fatty acid absorption in the small intestine. hsFATP4 was clearly expressed in both jejunum and ileum; expression was significantly lower in the colon and was absent in the stomach. This expression pattern is consistent with a major role for FATP4 in absorption of fatty acids in the human gut.

Example 10: Expression of hsFATP1 and hsFATP4 Promotes Transport of Fatty Acids

COS cells were cotransfected using lipofectamine with the mammalian expression vector pCDNA-CD2 in combination with one of the FATP-containing expression vectors (pMET7-hsFATP1 or pMET7-hsFATP4) or an insertless expression vector (pMET7, control) as described in Materials and Methods for Examples 6-10. COS cells were gated on forward scatter and side scatter. Cells exhibiting more than 400 CD2 fluorescence units representing ˜30% of all cells were deemed CD2-positive. The percent of CD2-positive cells exhibiting a BODIPY-fluorescence of >300 is plotted for the three different vectors tested (FIG. 37).

Example 11: Stable Expression of Human FATP4 in 293 Cells

Stable cell lines were generated as follows. A DNA fragment containing the entire hsFATP4 coding sequence as well as 100 nucleotides of 5′ and 50 nucleotides of 3′ untranslated region was inserted into the vector pIRES-neo (Clontech) using standard cloning techniques. The resulting construct or a vector control (pIRES-neo) was transfected into 293 cells using the lipofectamine method (Gibco BRL) according to the manufacturer's directions. Cells that had taken up the DNA were selected with 1 mg/ml G418 (Gibco BRL). Single colonies were picked 1 to 2 weeks after transfection and grown in medium containing 0.8 mg/ml G418. Colonies were screened for the ability to take up fatty acids by measuring uptake of a fluorescently labeled fatty acid (BODIPY-FA).

About 40 colonies transfected with the pIRES-neo containing FATP4 and ˜20 colonies transfected with pIRES-neo control were analyzed. All 20 of the vector control clones showed amounts of BODIFY-FA uptake similar to each other and to untransfected 293 cells. In contrast, among the 40 FATP4 transfected clones, 3 had a 5- to 10-fold increased BODIPY-FA uptake compared to any of the vector controls, and a large number (˜20) showed an approximately two-fold increase in BODIPY-FA levels. This distribution is consistent with FATP4 conferring increased fatty acid uptake in these cells. One of the cell lines with the highest amount of BODIPY-FA uptake was selected to be used for measuring uptake of tritiated fatty acid.

The uptake of tritiated oleate over time by either FATP4 expressing or control cells was assayed over time. Expression of FATP4 increases the rate of fatty acid uptake by over 3-fold, demonstrating that FATP4 is, like the other FATPs, a functional fatty acid transporter (FIG. 38).

Example 12: Immuno-staining with FATP4-Specific Antiserum

A polyclonal antiserum against the C-terminus of mmFATP4 was raised using a GST-fusion protein having mmFATP4-specific amino acid sequence 552-643 (AVASP . . . GEEKL). In western blot experiments, the purified antibody reacted strongly with a synthetic peptide matching the C-terminus of mmFATP4, but not with a corresponding region of mmFATP2, mmFATP3, or mmFATP5. The mmFATP4 specific polyclonal antiserum detects, in western blot experiments with enterocyte lysates from 3 different mice, a ˜70 kDa protein, which is in accordance with mmFATP4's predicted molecular weight of 72 kDa. The binding is specific for mmFATP4, since it can be completely abolished by preincubation of the antiserum with the GST-fusion peptide used to raise the antibody.

Immunofluorescence experiments were performed using the anti-mmFATP4 antiserum on fresh frozen sections of murine small intestine. The antibody binding demonstrates strong expression of mmFATP4 in enterocytes, confirming the results of the in situ hybridization experiments. At higher magnifications it is apparent that mmFATP4 is expressed at the apical side of the enterocyte, indicating that the transporter is present in the brush border membrane, which is known to mediate the uptake of fatty acids from the intestinal lumen.

Immuno-electron microscopy studies were performed on fresh frozen murine intestinal cells. The gold particles used, appearing as black specks on the electron micrographs, indicate the subcellular localization of mmFATP4 to be on the microvilli of the enterocyte. It can be seen from the electron micrographs that mmFATP4 is localized exclusively in membranes, preferentially the apical plasma membrane, confirming that it is indeed a membrane protein.

Example 13: Inhibition of Fatty Acid Uptake Specific to FATP4 Demonstrated in Isolated Mouse Enterocytes

Phosphorothioate derivatives of the following oligonucleotides were synthesized:

FATP4-AS2 CCCCCACCAGAGAGGCTCC (SEQ ID NO:103) FATP4- CCACCCCCGGAAAGCCTGC (SEQ ID NO:104) AS2MM FATP4-S2 GGAGCCTCTCTGGTGGGGG (SEQ ID NO:105)

FATP4 AS2 is the antisense oligo; it is designed to be complementary to the sequence extending from nucleotide 10 to nucleotide 28 of the mouse FATP4 coding sequence. FATP4-AS2MM is a control oligo; in the oligo every third nucleotide was changed creating mismatches; the overall nucleotide composition is identical to FATP4-AS2 (same number of G, A, T, C). FATP4-S2 is the sense control.

Enterocytes were isolated from the small intestine of mice and incubated for 48 h in tissue culture (FIG. 40) either without oligonucleotides (squares) or with 100 μM FATP4 specific sense (circles) or antisense (diamonds) oligonucleotides. The uptake over time of 25 μM oleate was then measured. While the FATP4 sense oligonucleotide did not significantly influence the uptake, the antisense oligonucleotide inhibited fatty acid uptake by ˜50%.

The effect of either FATP4 sense, antisense or mismatch sequence oligonucleotides on the uptake of fatty acids was measured in enterocytes. Isolated enterocytes were incubated with increasing concentrations of FATP4 antisense oligonucleotides (solid bars in FIG. 41), or a mismatch control oligonucleotide with identical nucleotide composition (stippled bars), or with 100 μM of the FATP4 sense-oligonucleotide (lined bar). The medium for this incubation was Dulbecco's modified Eagle's medium with 4.5 g/L glucose, 1 mM sodium pyruvate, 0.01 mg/ml human transferrin and 10% fetal bovine serum. After 48 hours of incubation the uptake of oleate by enterocytes was measured over a 5 minute time interval. Measurements were done in quadruplicate. The uptake assay was done in Hank's buffered salt solution with 10 mM taurocholate. Only the enterocytes given FATP4 antisense oligonucleotide showed a concentration dependent decrease of fatty acid uptake, inhibiting it at a 100 μM concentration by ˜50%. This effect was FATP4 specific, since only the antisense oligonucleotide which can bind to the FATP4 mRNA and block its translation inhibited uptake, but not a control oligonucleotide differing only in the sequence but not the nucleotide content, ruling out a toxic or otherwise nonspecific inhibitory effect of this oligonucleotide due to its chemical composition.

As a further control experiment, the uptake of oleate was measured along with the uptake of methionine in the same cultured enterocytes. Antisense oligonucleotide, mismatch sequence oligonucleotide, or no oligonucleotide was added to a concentration of 100 μM to cultures of enterocytes. After incubation for 48 hours, the uptake of both ³H-labeled oleate and ³⁵S-labeled methionine was assayed. Results are shown in FIG. 42. Fatty acid uptake is at the left side of the paired bars; methionine uptake is on the right side of the paired bars. The fact that amino acid uptake was not influenced by the antisense oligonucleotide treatment further supports the conclusion that the antisense oligonucleotide causes a specific reduction in translation of FATP4-specific mRNA.

Example 14: mmFATP2 Is Expressed in Proximal Renal Tubule Epithelium

Northern analysis showed that mmFATP 1, mmFATP2, and mmFATP4 are present in the kidney. In situ hybridization (methods as for Example 6) was performed to determine which cell type(s) of the kidney these mRNAs are expressed in. mmFATP1 mRNA was present in virtually all cells throughout the kidney with no obvious preference for a particular cell type. In contrast, mmFATP2 was expressed only in the renal cortex. Within the cortex, expression of mmFATP2 was restricted to the epithelial cells of the proximal renal tubules. The primary function of proximal renal tubule cells is the reabsorption of filtered salts and nutrients (e.g., glucose), a process that requires mitochondrial oxidation and that can utilize fatty acids as energy substrates. Based on the localization of mmFATP2, it is possible that mmFATP2 is important for reabsorption in the kidney by allowing uptake of an energy source (fatty acids) from the blood into renal epithelial cells. Alternatively, if fatty acids need to be reabsorbed in the kidney, similarly to glucose, FATP2 could be involved in the reabsorption of fatty acids. Determination of the subcellular localization of FATP2 will distinguish between these two possibilities.

Table 5 summarizes data on expression of the mouse FATPs in various organs.

TABLE 5 Mouse FATP mRNA Expression Mouse Probes mFATP1 mFATP2 mFATP3 mFATP4 mFATP5 E18.5 embryo everywhere, liver — Brain, small Mouse Probes expression brain = thymus > (hepatocytes) intestine, heart > brown superior fat, others cervical ganglion (SCG), dorsal root ganglion (DRG), other regions have lower expression Duodenum — villi (surface — villi (surface — epithelium) epithelium) Jejunum — villi (surface — villi (surface — epithelium) epithelium) Ileum — villi (surface — villi (surface — (epithelium) (epithelium) Colon low expression very low level — — — in the crypt in the crypt Kidney cortex and proximal — — — medulla tubules Liver — hepatocytes hepatocytes — hepatocytes Pancreas exocrine exocrine — — — secretory units secretory units or acinar cells; or acinar cells; endocrine endocrine pancreas (islet) pancreas (islet) are negative are negative Brain Neuronal — — Neuronal — expression expression throughout the throughout the brain including brain including hypothalamus hypothalamus Heart myocytes — — Testis seminiferous — seminiferous tubules tubules Lung bronchiole — — Adipose adipocyte adipocyte —

Example 15: Isolation of full-length human FATP3

Full-length clones encoding human FATP3 were identified by searching databases for sequences similar to the murine FATP1-5 coding regions using the BlastX algorithm (Altschul et al., J. Mol. Biol. 215: 403-410, 1990). Human clones with similarity to the 5′ end of murine FATP sequences were sequenced completely. A clone encoding full-length human FATP3 was obtained from a human bone library constructed in the mammalian expression vector pMET7 (Tartaglia, L. A. et al., Cell 83: 1263-1271, 1995). To identify human cDNA clones encoding FATP family members, databases were searched for sequences similar to murine FATP1-5 coding regions. One clone was found to encode the human ortholog of mmFATP3 and was designated hsFATP3. The DNA and predicted protein sequences of hsFATP3 are shown in FIGS. 94A-94J. hsFATP5 is predicted to encode a 703 amino acid 75.6 kD protein with multiple membrane-spanning domains. A comparison of the DNA sequences of mouse and human FATP3 shows that the mouse and human orthologs are 81 % identical to each other within the coding region. At the amino acid level, hsFATP3 is ˜86% identical to mm FATP3 within the coding region. The sequence identities between mouse and human FATP3 are considerably higher than those observed between part of the protein, a region that is poorly conserved between different FATP family members.

All references cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

105 1 340 PRT Mus musculus 1 Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Pro Ala Ile Leu 1 5 10 15 Ser His Glu Arg Val Ile Gln Val Ser Asn Val Leu Ser Phe Cys Gly 20 25 30 Cys Arg Ala Asp Asp Val Val Tyr Asp Val Leu Pro Leu Tyr His Thr 35 40 45 Ile Gly Leu Val Leu Gly Phe Leu Gly Cys Leu Gln Val Gly Ala Thr 50 55 60 Cys Val Leu Ala Pro Lys Phe Ser Ala Ser Arg Phe Trp Ala Glu Cys 65 70 75 80 Arg Gln His Gly Val Thr Val Ile Gln Tyr Ile Gly Glu Ile Cys Arg 85 90 95 Tyr Leu Leu Arg Gln Pro Val Arg Asp Val Glu Gln Arg His Arg Val 100 105 110 Arg Leu Ala Val Gly Asn Gly Leu Arg Pro Ala Ile Trp Glu Glu Phe 115 120 125 Thr Gln Arg Phe Gly Val Pro Gln Ile Gly Glu Phe Tyr Gly Ala Thr 130 135 140 Glu Cys Asn Cys Ser Ile Ala Asn Met Asp Gly Lys Val Gly Ser Cys 145 150 155 160 Gly Phe Asn Ser Arg Ile Leu Thr His Val Tyr Pro Ile Arg Leu Val 165 170 175 Lys Val Asn Glu Asp Thr Met Glu Pro Leu Arg Asp Ser Glu Gly Leu 180 185 190 Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Leu Leu Val Gly Gln Ile 195 200 205 Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly Tyr Val Ser Asp Ser 210 215 220 Ala Thr Asn Lys Lys Ile Ala His Ser Val Phe Arg Lys Gly Asp Ser 225 230 235 240 Ala Tyr Leu Ser Gly Asp Val Leu Val Met Asp Glu Leu Gly Tyr Met 245 250 255 Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe Arg Trp Arg Gly Glu Asn 260 265 270 Val Ser Thr Thr Glu Val Glu Ala Val Leu Ser Arg Leu Leu Gly Gln 275 280 285 Thr Asp Val Ala Val Tyr Gly Val Ala Val Pro Gly Val Glu Gly Lys 290 295 300 Ala Gly Met Ala Ala Ile Ala Asp Pro His Ser Gln Leu Asp Pro Asn 305 310 315 320 Ser Met Tyr Gln Glu Leu Gln Lys Val Leu Ala Ser Tyr Ala Arg Pro 325 330 335 Ile Phe Leu Arg 340 2 339 PRT Mus musculus 2 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Asn Pro Lys Pro Ala Val Ile 1 5 10 15 Lys His Phe Arg Tyr Phe Trp Ile Ala Met Gly Ala Gly Lys Ala Phe 20 25 30 Gly Ile Asn Lys Ser Asp Val Val Tyr Ile Thr Met Pro Met Tyr His 35 40 45 Ser Ala Ala Gly Ile Met Gly Ile Gly Ser Leu Ile Ala Phe Gly Ser 50 55 60 Thr Ala Val Ile Arg Lys Lys Phe Ser Ala Ser Asn Phe Trp Lys Asp 65 70 75 80 Cys Val Lys Tyr Asn Val Thr Ala Thr Leu Tyr Val Gly Glu Ile Leu 85 90 95 Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro Glu Asp Lys Ile His Thr 100 105 110 Val Arg Leu Ala Met Gly Thr Gly Leu Arg Ala Asn Val Trp Lys Asn 115 120 125 Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile Trp Glu Phe Tyr Gly Ser 130 135 140 Thr Glu Gly Asn Val Gly Leu Met Asn Tyr Val Gly His Cys Gly Ala 145 150 155 160 Val Gly Arg Thr Ser Cys Ile Leu Arg Met Leu Thr Pro Phe Glu Leu 165 170 175 Val Gln Phe Asp Ile Glu Thr Ala Glu Pro Leu Arg Asp Lys Gln Gly 180 185 190 Phe Cys Ile Pro Val Glu Pro Gly Lys Pro Gly Leu Leu Leu Thr Lys 195 200 205 Val Arg Lys Asn Gln Pro Phe Leu Gly Tyr Arg Gly Ser Gln Ala Glu 210 215 220 Ser Asn Arg Lys Leu Val Ala Asn Val Arg Arg Val Gly Asp Leu Tyr 225 230 235 240 Phe Asn Thr Gly Asp Val Leu Thr Leu Asp Gln Glu Gly Phe Phe Tyr 245 250 255 Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val 260 265 270 Ser Thr Gly Glu Val Glu Cys Val Leu Ser Ser Leu Asp Phe Leu Glu 275 280 285 Glu Val Asn Val Tyr Gly Val Pro Val Pro Gly Cys Glu Gly Lys Val 290 295 300 Gly Met Ala Ala Val Lys Leu Ala Pro Gly Lys Thr Phe Asp Gly Lys 305 310 315 320 Lys Tyr Gln His Val Arg Ser Trp Leu Pro Ala Tyr Ala Thr Pro His 325 330 335 Phe Ile Arg 3 345 PRT Caenorhabditis elegans 3 Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser 1 5 10 15 Trp Arg Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val Leu His 20 25 30 Met Thr Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu Phe His Ser 35 40 45 Thr Ala Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser His Gly Gly Cys 50 55 60 Leu Ala Leu Ser His Lys Phe Ser Ala Ser Thr Phe Trp Lys Gln Val 65 70 75 80 Tyr Leu Thr Gly Ala Thr His Ile Gln Tyr Ile Gly Glu Ile Cys Arg 85 90 95 Tyr Leu Leu Ala Ala Asn Pro Cys Pro Glu Glu Lys Gln His Asn Val 100 105 110 Arg Leu Met Trp Gly Asn Gly Leu Arg Gly Gln Ile Trp Lys Glu Phe 115 120 125 Val Gly Arg Phe Gly Ile Lys Lys Ile Gly Glu Leu Tyr Gly Ser Thr 130 135 140 Glu Gly Asn Ser Asn Ile Val Asn Val Asp Asn His Val Gly Ala Cys 145 150 155 160 Gly Phe Met Pro Ile Tyr Pro His Ile Gly Ser Leu Tyr Pro Val Arg 165 170 175 Leu Ile Lys Val Asp Arg Ala Thr Gly Glu Leu Glu Arg Asp Lys Asn 180 185 190 Gly Leu Cys Val Pro Cys Val Pro Gly Glu Thr Gly Glu Met Val Gly 195 200 205 Val Ile Lys Glu Lys Asp Ile Leu Leu Lys Phe Glu Gly Tyr Val Ser 210 215 220 Glu Gly Asp Thr Ala Lys Lys Ile Tyr Arg Asp Val Phe Lys His Gly 225 230 235 240 Asp Lys Val Phe Ala Ser Gly Asp Ile Leu His Trp Asp Asp Leu Gly 245 250 255 Tyr Leu Tyr Phe Val Asp Arg Cys Gly Asp Thr Phe Arg Trp Lys Gly 260 265 270 Glu Asn Val Ser Thr Thr Glu Val Glu Gly Ile Leu Gln Pro Val Met 275 280 285 Asp Val Glu Asp Ala Thr Val Tyr Gly Val Thr Val Gly Lys Met Glu 290 295 300 Gly Arg Ala Gly Met Ala Gly Ile Val Val Lys Asp Gly Thr Asp Val 305 310 315 320 Glu Lys Phe Ile Ala Asp Ile Thr Ser Arg Leu Thr Glu Asn Leu Ala 325 330 335 Ser Tyr Ala Ile Pro Val Phe Ile Arg 340 345 4 356 PRT Saccharomyces cerevisiae 4 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Ile Val 1 5 10 15 Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe Gly His His Ser Tyr 20 25 30 Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys Leu Pro Leu Tyr His 35 40 45 Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys Val Ile Tyr Gly Leu 50 55 60 Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp Asp Asp 65 70 75 80 Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr Val Gly Glu Val Cys 85 90 95 Arg Tyr Leu Leu His Thr Pro Ile Ser Lys Tyr Glu Lys Met His Lys 100 105 110 Val Lys Val Ala Tyr Gly Asn Gly Leu Arg Pro Asp Ile Trp Gln Asp 115 120 125 Phe Arg Lys Arg Phe Asn Ile Glu Val Ile Gly Glu Phe Tyr Ala Ala 130 135 140 Thr Glu Ala Pro Phe Ala Thr Thr Thr Phe Gln Lys Gly Asp Phe Gly 145 150 155 160 Ile Gly Ala Cys Arg Asn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser 165 170 175 Phe Gln Gln Thr Leu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile 180 185 190 Tyr Arg Asn Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro 195 200 205 Gly Glu Met Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser 210 215 220 Phe Gln Gly Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val 225 230 235 240 Arg Asp Val Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu 245 250 255 Leu Lys Ala Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly 260 265 270 Asp Thr Phe Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val Glu 275 280 285 Asp Gln Leu Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val Leu Val 290 295 300 Val Gly Ile Lys Val Pro Lys Tyr Glu Gly Arg Ala Gly Phe Ala Val 305 310 315 320 Ile Lys Leu Thr Asp Asn Ser Leu Asp Ile Thr Ala Lys Thr Lys Leu 325 330 335 Leu Asn Asp Ser Leu Ser Arg Leu Asn Leu Pro Ser Tyr Ala Met Pro 340 345 350 Leu Phe Val Lys 355 5 334 PRT Mycobacterium tuberculosis 5 Tyr Ile Phe Thr Ser Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met 1 5 10 15 Thr His His Arg Trp Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly 20 25 30 Leu Arg Leu Lys Gly Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr 35 40 45 His Asn Asn Ala Leu Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly 50 55 60 Ala Thr Leu Ala Leu Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp 65 70 75 80 Glu Val Ile Ala Asn Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile 85 90 95 Cys Arg Tyr Leu Leu Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala His 100 105 110 Gln Val Arg Val Ile Cys Gly Asn Gly Leu Arg Pro Glu Ile Trp Asp 115 120 125 Glu Phe Thr Thr Arg Phe Gly Val Ala Arg Val Cys Glu Phe Tyr Ala 130 135 140 Ala Ser Glu Gly Asn Ser Ala Phe Ile Asn Ile Phe Asn Val Pro Arg 145 150 155 160 Thr Ala Gly Val Ser Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu 165 170 175 Asp Thr Gly Asp Pro Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val 180 185 190 Pro Asp Gly Glu Pro Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln 195 200 205 Pro Phe Asp Gly Tyr Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val 210 215 220 Arg Asn Ala Phe Arg Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val 225 230 235 240 Met Ser Pro Gln Gly Met Gly His Ala Ala Phe Val Asp Arg Leu Gly 245 250 255 Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu 260 265 270 Ala Ala Leu Ala Ser Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly 275 280 285 Val Gln Ile Pro Arg Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr 290 295 300 Leu Arg Ala Gly Ala Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val 305 310 315 320 Tyr Gly His Leu Pro Gly Tyr Ala Leu Pro Leu Phe Val Arg 325 330 6 2087 DNA Mus musculus 6 acgactcact atagggagag agctatgacg tcgcatgcac gcgtaagctt gggcccctcg 60 agggatcctc tagagcggcc gccgaccccg aaagctctga gagcgggtgc agtctggcct 120 ggcgtctcgc gtacctggcc cgggagcagc cgacacacac cttcctcatc cacggcgcgc 180 agcgctttag ctacgcggag gctgagcgcg agagcaaccg gattgctcgc gcctttctgc 240 gcgcacgggg ctggaccggg ggccgccgag gctcgggcag gggcagcact gaggaaggcg 300 cacgcgtggc gcctccggct ggagatgcgg ctgctagagg gacgaccgcg ccccctctgg 360 cacccggggc gaccgtggcg ctgctcctcc cagcgggccc ggatttcctt tggatttggt 420 tcggactggc caaagctggc ctgcgcacgg cctttgtgcc caccgcttta cgccgaggac 480 ccctgctgca ctgcctccgc agctgcggtg cgagtgcgct cgtgctggcc acagagttcc 540 tggagtccct ggagccggac ctgccggcct tgagagccat ggggctccac ctatgggcga 600 cgggccctga aactaatgta gctggaatca gcaatttgct atcggaagca gcagaccaag 660 tggatgagcc agtgccgggg tacctctctg ccccccagaa cataatggac acctgcctgt 720 acatcttcac ctctggcact actggcctgc ccaaggctgc tcgaatcagt catctgaagg 780 ttctacagtg ccagggattc taccatctgt gtggagtcca ccaggaggac gtgatctacc 840 tcgcactccc actgtaccac atgtctggct cccttctggg cattgtgggc tgcttgggca 900 ttggggccac cgtggtgctg aaacccaagt tctcagctag ccagttctgg gacgattgcc 960 agaaacacag ggtgacagtg ttccagtaca ttggggagtt gtgccgatac ctcgtcaacc 1020 agcccccgag caaggcagag tttgaccata aggtgcgctt ggcagtgggc agtgggttgc 1080 gcccagacac ctgggagcgt ttcctgcggc gatttggacc tctgcagata ctggagacgt 1140 atggcatgac agagggcaac gtagctacgt tcaattacac aggacggcag ggtgcagtgg 1200 ggcgagcttc ctggctttac aagcacatct tccccttctc cttgattcga tacgatgtca 1260 tgacagggga gcctattcgg aatgcccagg ggcactgcat gaccacatct ccaggtgagc 1320 caggcctact ggtggcccca gtgagccagc agtccccctt cctgggctat gctggggctc 1380 cggagctggc caaggacaag ctgctgaagg atgtcttctg gtctggggac gttttcttca 1440 atactgggga cctcttggtc tgtgatgagc aaggctttct tcacttccac gatcgtactg 1500 gagacaccat caggtggaag ggagagaatg tggccacaac tgaagtggct gaggtcttgg 1560 agaccctgga cttccttcag gaggtgaaca tctatggagt cacggtgcca gggcacgaag 1620 gcagggcagg catggcggcc ttggctctgc ggcccccgca ggctctgaac ctggtgcagc 1680 tctacagcca tgtttctgag aacttgccac cgtatgcccg acctcggttt ctcaggctcc 1740 aggaatcttt ggccactact gagaccttca aacagcagaa ggttaggatg gccaatgagg 1800 gctttgaccc cagtgtactg tctgacccac tctatgttct ggaccaagat ataggggcct 1860 acctgcccct cacacctgcc cggtacagtg ccctcctgtc tggagacctt cgaatctgaa 1920 accttccact tgagggaggg gctcggaggg tacaggccac catggctgca ccagggaggg 1980 ttttcgggta tcttttgtat atggagtcat tattttgtaa taaacagctg gagcttaaaa 2040 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 2087 7 613 PRT Mus musculus 7 Ala Ala Asp Pro Glu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 Leu Ala Tyr Leu Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 Gly Ala Gln Arg Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 Ile Ala Arg Ala Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 Gly Ser Gly Arg Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80 Ala Gly Asp Ala Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95 Gly Ala Thr Val Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105 110 Ile Trp Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115 120 125 Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly 130 135 140 Ala Ser Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro 145 150 155 160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp Ala Thr Gly 165 170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala 180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro Gln Asn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His Leu Lys Val Leu Gln Cys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His Met Ser Gly Ser Leu Leu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly Ala Thr Val Val Leu Lys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp Asp Asp Cys Gln Lys His Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly Glu Leu Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 Glu Phe Asp His Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335 Asp Thr Trp Glu Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345 350 Glu Thr Tyr Gly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355 360 365 Gly Arg Gln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile 370 375 380 Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile 385 390 395 400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro Gly Glu Pro Gly 405 410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala 420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu Leu Lys Asp Val Phe Trp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp Arg Thr Gly Asp Thr Ile Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala Thr Thr Glu Val Ala Glu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln Glu Val Asn Ile Tyr Gly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg Ala Gly Met Ala Ala Leu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn Leu Val Gln Leu Tyr Ser His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 Thr Glu Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575 Asp Pro Ser Val Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585 590 Gly Ala Tyr Leu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595 600 605 Gly Asp Leu Arg Ile 610 8 2301 DNA Mus musculus 8 cccacgcgtc cgcccacgcg tccggcatgg ccaagctggg cgtggaggcg gctctcatca 60 acaccaacct taggcgggat gccctgcgcc actgtcttga cacctcaaag gcacgagctc 120 tcatctttgg cagtgagatg gcctcagcta tctgtgagat ccatgctagc ctggagccca 180 cactcagcct cttctgctct ggatcctggg agcccagcac agtgcccgtc agcacagagc 240 atctggaccc tcttctggaa gatgccccga agcacctgcc cagtcaccca gacaagggtt 300 ttacagataa gctcttctac atctacacat cgggcaccac ggggctaccc aaagctgcca 360 ttgtggtgca cagcaggtat tatcgtatgg cttccctggt gtactatgga ttccgcatgc 420 ggcctgatga cattgtctat gactgcctcc ccctctacca ctcaagcagg aaacatcgtg 480 gggattggca gtgcttactc cacggcatga ctgtggtgat ccggaagaag ttctcagcct 540 cccggttctg ggatgattgt atcaagtaca actgcacagt ggtacagtac attggcgagc 600 tctgccgcta cctcctgaac cagccacccc gtgaggctga gtctcggcac aaggtgcgca 660 tggcactggg caacggtctc cggcagtcca tctggaccga cttctccagc cgtttccaca 720 tcccccaggt ggctgagttc tatggggcca ctgaatgcaa ctgtagcctg ggcaactttg 780 acagccgggt gggggcctgt ggcttcaata gccgcatcct gtcctttgtg taccctatcc 840 gtttggtacg tgtcaatgag gataccatgg aactgatccg gggacccgat ggagtctgca 900 ttccctgtca accaggtcag ccaggccagc tggtgggtcg catcatccag caggaccctc 960 tgcgccgttt cgacgggtac ctcaaccagg gtgccaacaa caagaagatt gctaatgatg 1020 tcttcaagaa gggggaccaa gcctacctca ctggtgacgt cctggtgatg gatgagctgg 1080 gttacctgta cttccgagat cgcactgggg acacgttccg ctggaaaggg gagaatgtat 1140 ctaccactga ggtggagggc acactcagcc gcctgcttca tatggcagat gtggcagttt 1200 atggtgttga ggtgccagga actgaaggcc gagcaggaat ggctgccgtt gcaagtccca 1260 tcagcaactg tgacctggag agctttgcac agaccttgaa aaaggagctg cctctgtatg 1320 cccgccccat cttcctgcgc ttcttgcctg agctgcacaa gacagggacc ttcaagttcc 1380 agaagacaga gttgcggaag gagggctttg acccatctgt tgtgaaagac ccgctgttct 1440 atctggatgc tcggaagggc tgctacgttg cactggacca ggaggcctat acccgcatcc 1500 aggcaggcga ggagaagctg tgatttcccc ctacatccct ctgagggcca gaagatgctg 1560 gattcagagc cctagcgtcc accccagagg gtcctgggca atgccagacc aaagctagca 1620 gggcccgcac ctccgcccct aggtgctgat ctcccctctc ccaaactgcc aagtgactca 1680 ctgccgcttc cccgaccctc cagaggcttt ctgtgaaagt ctcatccaag ctgtgtcttc 1740 tggtccaggc gtggcccctg gccccagggt ttctgatagg ctcctttagg atggtatctt 1800 gggtccagcg ggccagggtg tgggagagga gtcactaaga tccctccaat cagaagggag 1860 cttacaaagg aaccaaggca aagcctgtag actcaggaag ctaagtggcc agagactata 1920 gtggccagtc atcccatgtc cacagaggat cttggtccag agctgccaaa gtgtcacctc 1980 tccctgcctg cacctctggg gaaaagagga cagcatgtgg ccactgggca cctgtctcaa 2040 gaagtcagga tcacacactc agtccttgtt tctccaggtt cccttgttct tgtctcgggg 2100 agggagggac gagtgtcctg tctgtccttc ctgcctgtct gtgagtctgt gttgcttctc 2160 catctgtcct agcctgagtg tgggtggaac aggcatgagg agagtgtggc tcaggggcca 2220 ataaactctg ccttgactcc tcttaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2280 aaaaaaaaaa aaaaaaaaaa a 2301 9 506 PRT Mus musculus 9 His Ala Ser Ala His Ala Ser Gly Met Ala Lys Leu Gly Val Glu Ala 1 5 10 15 Ala Leu Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu 20 25 30 Asp Thr Ser Lys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser 35 40 45 Ala Ile Cys Glu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe 50 55 60 Cys Ser Gly Ser Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His 65 70 75 80 Leu Asp Pro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro 85 90 95 Asp Lys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110 Thr Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 115 120 125 Met Ala Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130 135 140 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly 145 150 155 160 Asp Trp Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys 165 170 175 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr 180 185 190 Val Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro 195 200 205 Pro Arg Glu Ala Glu Ser Arg His Lys Val Arg Met Ala Leu Gly Asn 210 215 220 Gly Leu Arg Gln Ser Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile 225 230 235 240 Pro Gln Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu 245 250 255 Gly Asn Phe Asp Ser Arg Val Gly Ala Cys Gly Phe Asn Ser Arg Ile 260 265 270 Leu Ser Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr 275 280 285 Met Glu Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro 290 295 300 Gly Gln Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu 305 310 315 320 Arg Arg Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 325 330 335 Ala Asn Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 340 345 350 Val Leu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360 365 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 370 375 380 Glu Gly Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr 385 390 395 400 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val 405 410 415 Ala Ser Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu 420 425 430 Lys Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu 435 440 445 Pro Glu Leu His Lys Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu 450 455 460 Arg Lys Glu Gly Phe Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr 465 470 475 480 Leu Asp Ala Arg Lys Gly Cys Tyr Val Ala Leu Asp Gln Glu Ala Tyr 485 490 495 Thr Arg Ile Gln Ala Gly Glu Glu Lys Leu 500 505 10 2277 DNA Mus musculus 10 cactcatcag agctaagaga gactacacgc tctcatctac ttcagaaaga gccaatgcca 60 tgggtatttg gaagaaacta accttactgc tgttgctgct tctgctggtt ggcctggggc 120 agcccccatg gccagcagct atggctctgg ccctgcgttg gttcctggga gaccccacat 180 gccttgtgct gcttggcttg gcattgctgg gcagaccctg gatcagctcc tggatgcccc 240 actggctgag cctggtagga gcagctctta ccttattcct attgcctcta cagccacccc 300 cagggctacg ctggctgcat aaagatgtgg ctttcacctt caagatgctt ttctatggcc 360 taaagttcag gcgacgcctt aacaaacatc ctccagagac ctttgtggat gctttagagc 420 ggcaagcact ggcatggcct gaccgggtgg ccttggtgtg tactgggtct gagggctcct 480 caatcacaaa tagccagctg gatgccaggt cctgtcaggc agcatgggtc ctgaaagcaa 540 agctgaagga tgccgtaatc cagaacacaa gagatgctgc tgctatctta gttctcccgt 600 ccaagaccat ttctgctttg agtgtgtttc tggggttggc caagttgggc tgccctgtgg 660 cctggatcaa tccacacagc cgagggatgc ccttgctaca ctctgtacgg agctctgggg 720 ccagtgtgct gattgtggat ccagacctcc aggagaacct ggaagaagtc cttcccaagc 780 tgctagctga gaacattcac tgcttctacc ttggccacag ctcacccacc ccgggagtag 840 aggctctggg agcttccctg gatgctgcac cttctgaccc agtacctgcc agccttcgag 900 ctacgattaa gtggaaatct cctgccatat tcatctttac ttcagggacc actggactcc 960 caaagccagc catcttatca catgagcggg tcatacaagt gagcaacgtg ctgtccttct 1020 gtggatgcag agctgatgat gtggtctatg acgtcctacc tctgtaccat acgatagggc 1080 ttgtccttgg attccttggc tgcttacaag ttggagccac ctgtgtcctg gcccccaagt 1140 tctctgcctc ccgattctgg gctgagtgcc ggcagcatgg cgtaacagtg atcttgtatg 1200 tgggtgaaat cctgcggtac ttgtgtaacg tccctgagca accagaagac aagatacata 1260 cagtgcgctt ggccatggga actggacttc gggcaaatgt gtggaaaaac ttccagcaac 1320 gctttggtcc cattcggatc tgggaattct acggatccac agagggcaat gtgggcttaa 1380 tgaactatgt gggccactgc ggggctgtgg gaaggaccag ctgcatcctt cgaatgctga 1440 ctccctttga gcttgtacag ttcgacatag agacagcaga gcctctgagg gacaaacagg 1500 gtttttgcat tcctgtggag ccaggaaagc caggacttct tttgaccaag gttcgaaaga 1560 accaaccctt cctgggctac cgtggttccc aggccgagtc caatcggaaa cttgttgcga 1620 atgtacgacg cgtaggagac ctgtacttca acactgggga cgtgctgacc ttggaccagg 1680 aaggcttctt ctactttcaa gaccgccttg gtgacacctt ccggtggaag ggcgaaaacg 1740 tatctactgg agaggtggag tgtgttttgt ctagcctaga cttcctagag gaagtcaatg 1800 tctatggtgt gcctgtgcca gggtgtgagg gtaaggttgg catggctgct gtgaaactgg 1860 ctcctgggaa gacttttgat gggcagaagc tataccagca tgtccgctcc tggctccctg 1920 cctatgccac acctcatttc atccgtatcc aggattccct ggagatcaca aacacctaca 1980 agctggtaaa gtcacggctg gtgcgtgagg gttttgatgt ggggatcatt gctgaccccc 2040 tctacatact ggacaacaag gcccagacct tccggagtct gatgccagat gtgtaccagg 2100 ctgtgtgtga aggaacctgg aatctctgac cacctagcca actggaaggc aatccaaaag 2160 tgtagagatt gacactagtc agcttcacaa agttgtccgg gttccagatg cccatggccc 2220 agtagtactt agagaataaa cttgaatgtg tatacaaaaa aaaaaaaaaa aaaaaaa 2277 11 662 PRT Mus musculus 11 Met Ala Leu Ala Leu Arg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val 1 5 10 15 Leu Leu Gly Leu Ala Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met 20 25 30 Pro His Trp Leu Ser Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu 35 40 45 Pro Leu Gln Pro Pro Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala 50 55 60 Phe Thr Phe Lys Met Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu 65 70 75 80 Asn Lys His Pro Pro Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala 85 90 95 Leu Ala Trp Pro Asp Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly 100 105 110 Ser Ser Ile Thr Asn Ser Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala 115 120 125 Trp Val Leu Lys Ala Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg 130 135 140 Asp Ala Ala Ala Ile Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu 145 150 155 160 Ser Val Phe Leu Gly Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile 165 170 175 Asn Pro His Ser Arg Gly Met Pro Leu Leu His Ser Val Arg Ser Ser 180 185 190 Gly Ala Ser Val Leu Ile Val Asp Pro Asp Leu Gln Glu Asn Leu Glu 195 200 205 Glu Val Leu Pro Lys Leu Leu Ala Glu Asn Ile His Cys Phe Tyr Leu 210 215 220 Gly His Ser Ser Pro Thr Pro Gly Val Glu Ala Leu Gly Ala Ser Leu 225 230 235 240 Asp Ala Ala Pro Ser Asp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile 245 250 255 Lys Trp Lys Ser Pro Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly 260 265 270 Leu Pro Lys Pro Ala Ile Leu Ser His Glu Arg Val Ile Gln Val Ser 275 280 285 Asn Val Leu Ser Phe Cys Gly Cys Arg Ala Asp Asp Val Val Tyr Asp 290 295 300 Val Leu Pro Leu Tyr His Thr Ile Gly Leu Val Leu Gly Phe Leu Gly 305 310 315 320 Cys Leu Gln Val Gly Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala 325 330 335 Ser Arg Phe Trp Ala Glu Cys Arg Gln His Gly Val Thr Val Ile Leu 340 345 350 Tyr Val Gly Glu Ile Leu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro 355 360 365 Glu Asp Lys Ile His Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg 370 375 380 Ala Asn Val Trp Lys Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile 385 390 395 400 Trp Glu Phe Tyr Gly Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr 405 410 415 Val Gly His Cys Gly Ala Val Gly Arg Thr Ser Cys Ile Leu Arg Met 420 425 430 Leu Thr Pro Phe Glu Leu Val Gln Phe Asp Ile Glu Thr Ala Glu Pro 435 440 445 Leu Arg Asp Lys Gln Gly Phe Cys Ile Pro Val Glu Pro Gly Lys Pro 450 455 460 Gly Leu Leu Leu Thr Lys Val Arg Lys Asn Gln Pro Phe Leu Gly Tyr 465 470 475 480 Arg Gly Ser Gln Ala Glu Ser Asn Arg Lys Leu Val Ala Asn Val Arg 485 490 495 Arg Val Gly Asp Leu Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp 500 505 510 Gln Glu Gly Phe Phe Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg 515 520 525 Trp Lys Gly Glu Asn Val Ser Thr Gly Glu Val Glu Cys Val Leu Ser 530 535 540 Ser Leu Asp Phe Leu Glu Glu Val Asn Val Tyr Gly Val Pro Val Pro 545 550 555 560 Gly Cys Glu Gly Lys Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly 565 570 575 Lys Thr Phe Asp Gly Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu 580 585 590 Pro Ala Tyr Ala Thr Pro His Phe Ile Arg Ile Gln Asp Ser Leu Glu 595 600 605 Ile Thr Asn Thr Tyr Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly 610 615 620 Phe Asp Val Gly Ile Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys 625 630 635 640 Ala Gln Thr Phe Arg Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys 645 650 655 Glu Gly Thr Trp Asn Leu 660 12 1622 DNA Homo sapiens misc_feature (1)...(1622) n = A,T,C or G 12 atgggattga ctctttcctg gacaaagtgg atgaagtatc aactgaacct atcccagagt 60 catggaggtc tgaagtcact ttttccactc ctgccttata catttatact tctggaacca 120 caggtcttcc aaaagcagcc atgatcactc atcagcgcat atggtatgga actggcctca 180 cttttgtaag cggattgaag gcagatgatg tcatctatat cactctgccc ttttaccaca 240 gtgctgcact actgattggc attcacggat gtattgtggc tggtgctact cttgccttgc 300 ggactaaatt ttcagccagc cagttttggg atgactgcag aaaatacaac gtcactgtca 360 ttcagtatat cggtgaactg cttcggtatt tatgcaactc accacagaaa ccaaatgacc 420 gtgatcataa agtgagactg gcactgggaa atggcttacg aggagatgtg tggagacaat 480 ttgtcaagag atttggggac atatgcatct atgagttcta tgctgccact gaaggcaata 540 ttggatttat gaattatgcg agaaaagttg gtgctgttgg aagagtaaac tacctacaga 600 aaaaaatcat aacttatgac ctgattaaat atgatgtgga gaaagatgaa cctgtccgtg 660 atgaaaatgg atattgcgtc agagttccca aaggtgaagt tggacttctg gtttgcaaaa 720 tcacacaact tacaccattt aatggctatg ctggagcaaa ggctcagaca gagaagaaaa 780 aactgagaga tgtctttaag aaaggagacc tctatttcaa cagtggagat ctcttaatgg 840 ttgaccatga aaatttcatc tatttccacg acagagttgg agatacattc cggtggaaag 900 gggaaaatgt ggccaccact gaagttgctg atatagttgg actggttgat ttttttccaa 960 ggaagtaaaa tgtttatggg agtgcatggg ccaagatnat ggaggttcga attggcatgg 1020 cnttccnttc aaaatggaaa gaaaaccatg gaatttgatg gaaagaaatt ttttcagnac 1080 attgctgata accnacctag ttatgcaagg ccccggtttt ntaagaanac aggacaccat 1140 tgagatcact ggaattttta aacaccgcaa aatgaccttt ggtggaggag ggctttaacc 1200 cngctgtcat caaagatgcc ttgtattttc ttggatgaca cagcaaaaat gtatgtgcct 1260 atgactgagg acatntataa tgccataagt gntaaaaccc tgaaattntg aatattccca 1320 ggaggataat tcaacatttc cagaaagaaa ctgaatggac agccacttga tataatccaa 1380 ctttaatttg attgaagatt gtgaggaaat tttgtaggaa atttgcatac ccgtaaaggg 1440 agactttttt aaataacagt tgagtctttg caagtaaaaa gatttagaga ttattatttt 1500 tcagtgtgca cctactgttt gtatttgcaa actgagcttg ttggagggaa ggcattattt 1560 tttaaaatac ttagtaaatt aaagaacacc aacatgtgaa aaaaaaaaaa aaaaaaaaaa 1620 aa 1622 13 286 PRT Homo sapiens 13 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Met Ile 1 5 10 15 Thr His Gln Arg Ile Trp Tyr Gly Thr Gly Leu Thr Phe Val Ser Gly 20 25 30 Leu Lys Ala Asp Asp Val Ile Tyr Ile Thr Leu Pro Phe Tyr His Ser 35 40 45 Ala Ala Leu Leu Ile Gly Ile His Gly Cys Ile Val Ala Gly Ala Thr 50 55 60 Leu Ala Leu Arg Thr Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys 65 70 75 80 Arg Lys Tyr Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg 85 90 95 Tyr Leu Cys Asn Ser Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val 100 105 110 Arg Leu Ala Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Gln Phe 115 120 125 Val Lys Arg Phe Gly Asp Ile Cys Ile Tyr Glu Phe Tyr Ala Ala Thr 130 135 140 Glu Gly Asn Ile Gly Phe Met Asn Tyr Ala Arg Lys Val Gly Ala Val 145 150 155 160 Gly Arg Val Asn Tyr Leu Gln Lys Lys Ile Ile Thr Tyr Asp Leu Ile 165 170 175 Lys Tyr Asp Val Glu Lys Asp Glu Pro Val Arg Asp Glu Asn Gly Tyr 180 185 190 Cys Val Arg Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys Ile 195 200 205 Thr Gln Leu Thr Pro Phe Asn Gly Tyr Ala Gly Ala Lys Ala Gln Thr 210 215 220 Glu Lys Lys Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Leu Tyr Phe 225 230 235 240 Asn Ser Gly Asp Leu Leu Met Val Asp His Glu Asn Phe Ile Tyr Phe 245 250 255 His Asp Arg Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 260 265 270 Thr Thr Glu Val Ala Asp Ile Val Gly Leu Val Asp Phe Phe 275 280 285 14 753 DNA Homo sapiens 14 caattcggga cccccagggg cactgtatgg ccacatctcc aggtgagcca ggggaagttg 60 ctaaaggatg tcttccggcc tggggatgtt ttcttcaaca ctggggacct gctggtctgc 120 gatgaccaag gttttctccg cttccatgat cgtactggag acaccttcag gtggaaaggg 180 gagaatgtgg ccacaaccga ggtggcagag gtcttcgagg ccctagattt tcttcaggag 240 gtgaacgtct atggagtcac tgtgccaggg catgaaggca gggctggaat ggcagcccta 300 gttctgcgtc ccccccacgc tttggacctt atgcagctct acacccacgt gtctgagaac 360 ttgccacctt atgcccggcc ccgattcctc aggctccagg agtctttggc caccacagag 420 accttcaaac agcagaaagt tcggatggca aatgagggct tcgaccccag caccctgtct 480 gacccactgt acgttctgga ccaggctgta ggtgcctacc tgcccctcac aactgcccgg 540 tacagcgccc tcctggcagg aaaccttcga atctgagaac ttccacacct gaggcacctg 600 agagaggaac tctgtggggt gggggccgtt gcaggtgtac tgggctgtca gggatctttt 660 ctataccaga actgcggtca ctattttgta ataaatgtgg ctggagctga tccagctgtc 720 tctgacctac aaaaaaaaaa aaaaaaaaaa aaa 753 15 191 PRT Homo sapiens 15 Gln Phe Gly Thr Pro Arg Gly Thr Val Trp Pro His Leu Gln Val Ser 1 5 10 15 Gln Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly Asp Val Phe Phe 20 25 30 Asn Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly Phe Leu Arg Phe 35 40 45 His Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 50 55 60 Thr Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu 65 70 75 80 Val Asn Val Tyr Gly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly 85 90 95 Met Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln 100 105 110 Leu Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg 115 120 125 Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln 130 135 140 Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser 145 150 155 160 Asp Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro Leu 165 170 175 Thr Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile 180 185 190 16 734 DNA Homo sapiens misc_feature (1)...(734) n = A,T,C or G 16 tcaagtacaa ctgcacgatt gtcatancat tggtgaactg tgccgntacc tcctgaacca 60 gccaccgcgg gaggcagaaa accagcacca ggttcgcatg gcactaggca atggcctccg 120 gcagtccatc tggaccaact tttccagccg cttccacata ccccaggtgg ctgagttyta 180 cggggccaca gagtgcaact gtagcctggg caacttcgac agccaggtgg gggcctgtgg 240 tttcaatagc cgcatcctgt ccttcgtgta ccccatccgg ttggtacgtg tcaacgagga 300 caccatggag ctgatccggg ggcccgacgg cgtctgcatt ccctgccagc caggtgagcc 360 gggccagctg gtgggccgca tcatccagaa agaccccctg cgccgcttcg atggctacct 420 caaccagggc gccaacaaca agaagattgc caaggatgtc ttcaagaagg gggaccaggc 480 ctaccttact ggtgatgtgc tggtgatgga cgagctgggc tacctgtact tccgagaccg 540 cactggggac acgttccgct ggaaaggtga gaacgtgtcc accaccgagg tggaaggcac 600 actcagccgc ctgctggaca tggctgacgt ggccgtgtat ggtgtcgagg tgccaggaac 660 cgagggccgg gccggaatgg ctgctgtggc cagccccact ggcaactgtg acctgggagc 720 gctttgctca ggtc 734 17 213 PRT Homo sapiens 17 Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala 1 5 10 15 Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln 20 25 30 Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala 35 40 45 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp 50 55 60 Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val 65 70 75 80 Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile 85 90 95 Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 100 105 110 Gln Leu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp 115 120 125 Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val 130 135 140 Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met 145 150 155 160 Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe 165 170 175 Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu 180 185 190 Ser Arg Leu Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val 195 200 205 Pro Gly Thr Glu Gly 210 18 1278 DNA Homo sapiens misc_feature (1)...(1278) n = A,T,C or G 18 cntgcctctt gtaccacgtg atgggacttt gtcgttggga tcctcggctg cttagatctc 60 ggagccacct gtgttctggc ccccaagttc tctacttcct gcttctggga tgactgtcgg 120 cagcatggcg tgacagtgat cctgtatgtg ggcgagctcc tgcgntactt gtgtaacatt 180 ccccagcaac cagaggaccg gacacataca gtccgcctgg caatgggcaa tggactacgg 240 gctgatgtgt ggggagacct tccagcagcg tttcggtcct atttcggatc tngggaagtc 300 ttacgggcty ccacagaagg gcaacatggg gctttagttc aactattgtt gggggcgctg 360 cggggscctg grggcaaaga tggagcttgc ctcctccgaa tgctgtcccc ctttgagctg 420 gtgcagttcg acatggaggc ggcggagcct gtgagggaca atcagggctt ctgcatccct 480 gtagggctag gggagccggg gctgctgttg accaaggtgg taagccagca acccttcgtg 540 ggctaccgcg gcccccgaga gctgtcggaa cggaagctgg tgcgcaacgt gcggcaatcg 600 ggcgacgttt actacaacac cggggacgta ctggccatgg accgcgaagg cttcctctac 660 ttccgcgacc gactcgggga caccttccga tggaagggcg agaacgtgtc cacgcacgag 720 gtggagggcg tgttgtcgca ggtggacttc ttgcaacagg ttaacgtgta tggcgtgtgc 780 gtgccaggtt gtgagggtaa ggtgggcatg gctgctgtgg cattagcccc cggccagact 840 ttcgacgggg agaagttgta ccagcacgtt cgcgcttggc tccctgccta cgctaccccc 900 catttcatcc gcatccagga cgccatggag gtcaccagca cgttcaaact gatgaagacc 960 cggttggtgc gtgagggctt caatgtgggg atcgtggttg accctctgtt tgtactggac 1020 aaccgggccc agtccttccg gcccctgacg gcagaaatgt accaggctgt gtgtgaggga 1080 acctggaggc tctgatcacc tggccaaccc actggggtag ggatcaaagc cagccacccc 1140 caccccaaca cactcggtgt ccctttcatc ctgggcctgt gtgaatccca gcctggccat 1200 accctcaacc tcagtgggct ggaaatgaca gtgggccctg tagcagtggc agaataaact 1260 cagmtgygtt cacagaaa 1278 19 199 PRT Homo sapiens 19 Glu Gly Gln His Gly Ala Leu Val Gln Leu Leu Leu Gly Ala Leu Arg 1 5 10 15 Gly Pro Gly Gly Lys Asp Gly Ala Cys Leu Leu Arg Met Leu Ser Pro 20 25 30 Phe Glu Leu Val Gln Phe Asp Met Glu Ala Ala Glu Pro Val Arg Asp 35 40 45 Asn Gln Gly Phe Cys Ile Pro Val Gly Leu Gly Glu Pro Gly Leu Leu 50 55 60 Leu Thr Lys Val Val Ser Gln Gln Pro Phe Val Gly Tyr Arg Gly Pro 65 70 75 80 Arg Glu Leu Ser Glu Arg Lys Leu Val Arg Asn Val Arg Gln Ser Gly 85 90 95 Asp Val Tyr Tyr Asn Thr Gly Asp Val Leu Ala Met Asp Arg Glu Gly 100 105 110 Phe Leu Tyr Phe Arg Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly 115 120 125 Glu Asn Val Ser Thr His Glu Val Glu Gly Val Leu Ser Gln Val Asp 130 135 140 Phe Leu Gln Gln Val Asn Val Tyr Gly Val Cys Val Pro Gly Cys Glu 145 150 155 160 Gly Lys Val Gly Met Ala Ala Val Ala Leu Ala Pro Gly Gln Thr Phe 165 170 175 Asp Gly Glu Lys Leu Tyr Gln His Val Arg Ala Trp Leu Pro Ala Tyr 180 185 190 Ala Thr Pro His Phe Ile Arg 195 20 1361 DNA Homo sapiens 20 cgcttgtgtg ttaaagaaga aattttcagc aagccagttt tggagtgact gcaagaagta 60 tgatgtgact gtgtttcagt atattggaga actttgtcgc tacctttgca aacaatctaa 120 gagagaagga gaaaaggatc ataaggtgcg tttggcaatt ggaaatggca tacggagtga 180 tgtatggaga gaatttttag acagatttgg aaatataaag gtgtgtgaac tttatgcagc 240 taccgaatca agcatatctt tcatgaacta cactgggaga attggagcaa ttgggagaac 300 aaatttgttt tacaaacttc tttccacttt tgacttaata aagtatgact ttcagaaaga 360 tgaacccatg agaaatgagc agggttgggt attcatgaga aaaaggagac ctggacttct 420 catttctcga gtgaatgcaa aaaatccctt ctttggctat gctgggcctt ataagcacac 480 aaaagacaaa ttgctttgtg atgtttttaa gaagggagat gtttacctta atactggaga 540 cttaatagtc caggatcagg acaatttcct ttatttttgg gaccgtactg gagacacttt 600 cagatggaaa ggagaaaatg tcgcaaccac tgaggttgct gatgttattg gaatgttgga 660 tttcatacag gaagcaaacg tctatggtgt ggctatatca ggttatgaag gaagagcagg 720 aatggcttct attattttaa aaccaaatac atctttagat ttggaaaaag tttatgaaca 780 agttgtaaca tttctaccag cttatgcttg tccacgattt ttaagaattc aggaaaaaat 840 ggaagcaaca ggaacattca aactattgaa gcatcagttg gtggaagatg gatttaatcc 900 actgaaaatt tctgaaccac tttacttcat ggataacttg aaaaagtctt atgttctact 960 gaccagggaa ctttatgatc aaataatgtt aggggaaata aaactttaag atttttatat 1020 ctagaacttt catatgcttt cttaggaaga gtgagagggg ggtatatgat tctttatgaa 1080 atggggaaag ggagctaaca ttaattatgc atgtactata tttccttaat atgagagata 1140 attttttaat tgcataagaa ttttaatttc ttttaattga tataaacaga gttgattatt 1200 ctttttatct atttggagat tcagtgcata actaagtatt ttccttaata ctaaagattt 1260 taaataataa atagtggcta gcggtttgga caatcactaa aaatgtactt tctaataagt 1320 aaaatttcta attttgaata aaagattaaa ttttactgaa a 1361 21 335 PRT Homo sapiens 21 Ala Cys Val Leu Lys Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp 1 5 10 15 Cys Lys Lys Tyr Asp Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys 20 25 30 Arg Tyr Leu Cys Lys Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys 35 40 45 Val Arg Leu Ala Ile Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu 50 55 60 Phe Leu Asp Arg Phe Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala 65 70 75 80 Thr Glu Ser Ser Ile Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala 85 90 95 Ile Gly Arg Thr Asn Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu 100 105 110 Ile Lys Tyr Asp Phe Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly 115 120 125 Trp Val Phe Met Arg Lys Arg Arg Pro Gly Leu Leu Ile Ser Arg Val 130 135 140 Asn Ala Lys Asn Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr 145 150 155 160 Lys Asp Lys Leu Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu 165 170 175 Asn Thr Gly Asp Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe 180 185 190 Trp Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 195 200 205 Thr Thr Glu Val Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu 210 215 220 Ala Asn Val Tyr Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly 225 230 235 240 Met Ala Ser Ile Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys 245 250 255 Val Tyr Glu Gln Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg 260 265 270 Phe Leu Arg Ile Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu 275 280 285 Leu Lys His Gln Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser 290 295 300 Glu Pro Leu Tyr Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu 305 310 315 320 Thr Arg Glu Leu Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 325 330 335 22 2007 DNA Mycobacterium tuberculosis 22 tagtcgataa cgtcaaggac gctctgcggg cctgcgcacc ttcctgaggt tggtcgacaa 60 ccaattcgac atttcgcaaa cgaatcgagg gcttacgtgt ccgattacta cggcggcgca 120 cacacaacgg tcaggctgat cgacctggca actcggatgc cgcgagtgtt ggcggacacg 180 ccggtgattg tgcgtggggc aatgaccggg ctgctggccc ggccgaattc caaggcgtcg 240 atcggcacgg tgttccagga ccgggccgct cgctacggtg accgagtctt cctgaaattc 300 ggcgatcagc agctgaccta ccgcgacgct aacgccaccg ccaaccggta cgccgcggtg 360 ttggccgccc gcggcgtcgg ccccggcgac gtcgttggca tcatgttgcg taactcaccc 420 agcacagtct tggcgatgct ggccacggtc aagtgcggcg ctatcgccgg catgctcaac 480 taccaccagc gcggcgaggt gttggcgcac agcctgggtc tgctggacgc gaaggtactg 540 atcgcagagt ccgacttggt cagcgccgtc gccgaatgcg gcgcctcgcg cggccgggta 600 gcgggcgacg tgctgaccgt cgaggacgtg gagcgattcg ccacaacggc gcccgccacc 660 aacccggcgt cggcgtcggc ggtgcaagcc aaagacaccg cgttctacat cttcacctcg 720 ggcaccaccg gatttcccaa ggccagtgtc atgacgcatc atcggtggct gcgggcgctg 780 gccgtcttcg gagggatggg gctgcggctg aagggttccg acacgctcta cagctgcctg 840 ccgctgtacc acaacaacgc gttaacggtc gcggtgtcgt cggtgatcaa ttctggggcg 900 accctggcgc tgggtaagtc gttttcggcg tcgcggttct gggatgaggt gattgccaac 960 cgggcgacgg cgttcgtcta catcggcgaa atctgccgtt atctgctcaa ccagccggcc 1020 aagccgaccg accgtgccca ccaggtgcgg gtgatctgcg gtaacgggct gcggccggag 1080 atctgggatg agttcaccac ccgcttcggg gtcgcgcggg tgtgcgagtt ctacgccgcc 1140 agcgaaggca actcggcctt tatcaacatc ttcaacgtgc ccaggaccgc cggggtatcg 1200 ccgatgccgc ttgcctttgt ggaatacgac ctggacaccg gcgatccgct gcgggatgcg 1260 agcgggcgag tgcgtcgggt acccgacggt gaacccggcc tgttgcttag ccgggtcaac 1320 cggctgcagc cgttcgacgg ctacaccgac ccggttgcca gcgaaaagaa gttggtgcgc 1380 aacgcttttc gagatggcga ctgttggttc aacaccggtg acgtgatgag cccgcagggc 1440 atgggccatg ccgccttcgt cgatcggctg ggcgacacct tccgctggaa gggcgagaat 1500 gtcgccacca ctcaggtcga agcggcactg gcctccgacc agaccgtcga ggagtgcacg 1560 gtctacggcg tccagattcc gcgcaccggc gggcgcgccg gaatggccgc gatcacactg 1620 cgcgctggcg ccgaattcga cggccaggcg ctggcccgaa cggtttacgg tcacttgccc 1680 ggctatgcac ttccgctctt tgttcgggta gtggggtcgc tggcgcacac cacgacgttc 1740 aagagtcgca aggtggagtt gcgcaaccag gcctatggcg ccgacatcga ggatccgctg 1800 tacgtactgg ccggcccgga cgaaggatat gtgccgtact acgccgaata ccctgaggag 1860 gtttcgctcg gaaggcgacc gcagggctag cggattccgg gcgcagtctc gatacccgca 1920 ctggacgctc gacggtaacc aggcactatg gatgcgtgcg ttcaacaccg ccggcctcag 1980 ccggtcgttc aacaccgccg gcgttag 2007 23 597 PRT Mycobacterium tuberculosis 23 Met Ser Asp Tyr Tyr Gly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595 24 3704 DNA Homo sapiens CDS (175)...(2112) 24 tcgacccacg gcgtccggga ccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtcc aggagtctgc agaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcct gcctgagctt ctgggagact gaaggcacgg cttgcagctt cagg atg 177 Met 1 cgg gct ccg ggt gcg ggc gcg gcc tcg gtg gtc tcg ctg gcg ctg ttg 225 Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu Leu 5 10 15 tgg ctg ctg ggg ctg ccg tgg acc tgg agc gcg gca gcg gcg ctc ggc 273 Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu Gly 20 25 30 gtg tac gtg ggc agc ggc ggc tgg cgc ttc ctg cgc atc gtc tgc aag 321 Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys Lys 35 40 45 acc gcg agg cga gac ctc ttc ggt ctc tct gtg ctg atc cgc gtg cgc 369 Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val Arg 50 55 60 65 ctg gag ctg cgg cgg cac cag cgt gcc ggc cac acc atc ccg cgc atc 417 Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg Ile 70 75 80 ttt cag gcg gta gtg cag cga cag ccc gag cgc ctg gcg ctg gtg gat 465 Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val Asp 85 90 95 gcc ggg acc ggc gag tgc tgg acc ttt gcg cag ctg gac gcc tac tcc 513 Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr Ser 100 105 110 aat gcg gta gcc aac ctc ttc cgc cag ctg ggc ttc gcg ccg ggc gac 561 Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly Asp 115 120 125 gtg gtg gcc atc ttc ctg gag ggc cgg ccg gag ttc gtg ggg ctg tgg 609 Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu Trp 130 135 140 145 ctg ggc ctg gcc aag gcg ggc atg gag gcc gcg ctg ctc aac gtg aac 657 Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val Asn 150 155 160 ctg cgg cgc gag ccc ctg gcc ttc tgc ctg ggc acc tcg ggc gct aag 705 Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala Lys 165 170 175 gcc ctg atc ttt gga gga gaa atg gtg gcg gcg gtg gcc gaa gtg agc 753 Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val Ser 180 185 190 ggg cat ctg ggg aaa agt ttg atc aag ttc tgc tct gga gac ttg ggg 801 Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu Gly 195 200 205 ccc gag ggc atc ttg ccg gac acc cac ctc ctg gac ccg ctg ctg aag 849 Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu Lys 210 215 220 225 gag gcc tct act gcc ccc ttg gca cag atc ccc agc aag ggc atg gac 897 Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met Asp 230 235 240 gat cgt ctt ttc tac atc tac acg tcg ggg acc acc ggg ctg ccc aag 945 Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys 245 250 255 gct gcc att gtc gtg cac agc agg tac tac cgc atg gca gcc ttc ggc 993 Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe Gly 260 265 270 cac cac gcc tac cgc atg cag gcg gct gac gtg ctc tat gac tgc ctg 1041 His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys Leu 275 280 285 ccc ctg tac cac tcg gca gga aac atc atc ggc gtg ggg cag tgt ctc 1089 Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys Leu 290 295 300 305 atc tat ggg ctg aca gtc gtc ctc cgc aag aaa ttc tcg gcc agc cgc 1137 Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser Arg 310 315 320 ttc tgg gac gac tgc atc aag tac aac tgc acg gtg gtt cag tac atc 1185 Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile 325 330 335 ggg gag atc tgc cgc tac ctg ctg aag cag ccg gtg cgc gag gcg gag 1233 Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala Glu 340 345 350 agg cga cac cgc gtg cgc ctg gcg gtg ggg aac ggg ctg cgt cct gcc 1281 Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro Ala 355 360 365 atc tgg gag gag ttc acg gag cgc ttc ggc gta cgc caa atc ggg gag 1329 Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly Glu 370 375 380 385 ttc tac ggc gcc acc gag tgc aac tgc agc att gcc aac atg gac ggc 1377 Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp Gly 390 395 400 aag gtc ggc tcc tgt ggt ttc aac agc cgc atc ctg ccc cac gtg tac 1425 Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val Tyr 405 410 415 ccc atc cgg ctg gtg aag gtc aat gag gac aca atg gag ctg ctg cgg 1473 Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu Arg 420 425 430 gat gcc cag ggc ctc tgc atc ccc tgc cag gcc ggg gag cct ggc ctc 1521 Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly Leu 435 440 445 ctt gtg ggt cag atc aac caa cag gac ccg ctg cgc cgc ttc gat ggc 1569 Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly 450 455 460 465 tat gtc agc gag agc gcc acc agc aag aag atc gcc cac agc gtc ttc 1617 Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val Phe 470 475 480 agc aag ggc gac agc gcc tac ctc tca ggt gac gtg cta gtg atg gat 1665 Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met Asp 485 490 495 gag ctg ggc tac atg tac ttc cgg gac cgt agc ggg gac acc ttc cgc 1713 Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe Arg 500 505 510 tgg cga ggg gag aac gtc tcc acc acc gag gtg gag ggc gtg ctg agc 1761 Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu Ser 515 520 525 cgc ctg ctg ggc cag aca gac gtg gcc gtc tat ggg gtg gct gtt cca 1809 Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val Pro 530 535 540 545 gga gtg gag ggt aag gca ggg atg gcg gcc gtc gca gac ccc cac agc 1857 Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His Ser 550 555 560 ctg ctg gac ccc aac gcg ata tac cag gag ctg cag aag gtg ctg gca 1905 Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu Ala 565 570 575 ccc tat gcc cgg ccc atc ttc ctg cgc ctc ctg ccc cag gtg gac acc 1953 Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp Thr 580 585 590 aca ggc acc ttc aag atc cag aag acg agg ctg cag cga gag ggc ttt 2001 Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly Phe 595 600 605 gac cca cgc cag acc tca gac cgg ctc ttc ttc ctg gac ctg aag cag 2049 Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys Gln 610 615 620 625 ggc cac tac ctg ccc tta aat gag gca gtc tac act cgc atc tgc tcg 2097 Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys Ser 630 635 640 ggc gcc ttc gcc ctc tgaagctgtt cctctactgg ccacaaactc tgggcctggt 2152 Gly Ala Phe Ala Leu 645 gggagaggcc agcttgagcc agacagcgct gcccaggggt ggccgcctag tacacaccca 2212 cctggccgag ctgtacctgg cacggcccat cctggactga gaaactggaa cctcagagga 2272 acccgtgcct ctctgctgcc ttggtgcccc tgtgtctgcc tcctctccct gcttttcagc 2332 ctctgtctcc ttccatccct gtccctgtct ggccttaact cttccctctc tttcttttct 2392 ttctttcttt cttttttttt aagatagagt ctcactctgc tgcccgggct agagtgcagt 2452 ggtgggatct cggctcactg caacctctgc ctcctggggt tcaagtgatc ctcccacctc 2512 agcctcctga gtagctggga ttacaggcac ccgccaccac gtccagctaa tttttatatt 2572 tttagtagag acggggtttc accatgttgg tcaggctggt cttgaactcc tgacctcagg 2632 tgatccgctg gcctcggcct cccagagtgc tgggattata ggcgtgagcc tctggcccgg 2692 cctttccttt ttcctctcct ctcctgccga gagtggaaca cacgtgtcct gggagctgca 2752 tcttgtgtag ggtccagctg cttttgggga ctgcaggaat catctcccct gggccctgga 2812 ctcggactgg ggcctcccca cctccctctc ggctgtgcct tacggagccc caatccaggc 2872 ctcctgtggc tgttgggttc cagatgctgc agctccatgt gacttccaag caggccctcc 2932 gccctccctg ctgaatggag gagccggggg tcccccaggc caactggaaa atctcccagg 2992 ctaggccaat tgccttttgc acttccccgt tcctgtcaca tttccccagc cccaccttcc 3052 cctcctgatg ccctgaaagc ttccggaatt gactgtgacc acttggatgt caccactgtc 3112 agcccctgcc ttgatgtccc catttagcca tctccatgga gctcctgctg gagggccctg 3172 aaccctgcac tgcgtggctg cccagccagc tgcctcctgt cctgggagga ggcctcctgg 3232 gtgtcctcat ctggtgtgtc tactggaggg tcccacagga gaggcagcag aggggtcagg 3292 ggaggtctcc tgccgggggt tggcctctca agcctcaggg gttctagcct gttgaatata 3352 ccccacctgg tgggtggccc ctccgatgtc cccactgatg gctctgacac cgtgttggtg 3412 gcgatgtccc agacaatccc accaggacgg cccagacatc cctactggct tcgctggtgg 3472 ctcatctcga acatccacgc cagcctttct ggggccggcc acccaggccg cctgtccgtc 3532 tgtcctccct ccagcagcac cccctggccc ctggagtggt ggggccatgg caagagacac 3592 cgtggcgtct catgtgaact ttcctgggca ctgtggtttt atttcctaat tgatttaaga 3652 aataaacctg aagaccgtct ggtgaaaaaa aaaaaaaaaa aagggcggcc gc 3704 25 646 PRT Homo sapiens 25 Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 26 2917 DNA Homo sapiens CDS (208)...(2136) 26 cgacccacgc gtccgggcgg gcggggccgg gcggcgggcg gggctggcgg ggcggccggg 60 ccatgcaggg cgcagagccg gctaaaccct gctgagaccc ggctccgtgc gtccaggggc 120 ggctaatgcc cctcacgctg tctacgctgc tgcaaccggg ccgcatctgg acggggcgcc 180 gcgcggcgga gccgacgccg ggccaca atg ctg ctt gga gcc tct ctg gtg ggg 234 Met Leu Leu Gly Ala Ser Leu Val Gly 1 5 gtg ctg ctg ttc tcc aag ctg gtg ctg aaa ctg ccc tgg acc cag gtg 282 Val Leu Leu Phe Ser Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val 10 15 20 25 gga ttc tcc ctg ttg ttc ctc tac ttg gga tct ggc ggc tgg cgc ttc 330 Gly Phe Ser Leu Leu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe 30 35 40 atc cgg gtc ttc atc aag acc atc agg cgc gat atc ttt ggc ggc ctg 378 Ile Arg Val Phe Ile Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu 45 50 55 gtc ctc ctg aag gtg aag gca aag gtg cga cag tgc ctg cag gag cgg 426 Val Leu Leu Lys Val Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg 60 65 70 cgg aca gtg ccc att ttg ttt gcc tct acc gtt cgg cgc cac ccc gac 474 Arg Thr Val Pro Ile Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp 75 80 85 aag acg gcc ctg atc ttc gag ggc aca gat acc cac tgg acc ttc cgc 522 Lys Thr Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg 90 95 100 105 cag ctg gat gag tac tca agc agt gta gcc aac ttc ctg cag gcc cgg 570 Gln Leu Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg 110 115 120 ggc ctg gcc tcg ggc gat gtg gct gcc atc ttc atg gag aac cgc aat 618 Gly Leu Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn 125 130 135 gag ttc gtg ggc cta tgg ctg ggc atg gcc aag ctc ggt gtg gag gca 666 Glu Phe Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala 140 145 150 gcc ctc atc aac acc aac ctg cgg cgg gat gct ctg ctc cac tgc ctc 714 Ala Leu Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu 155 160 165 acc acc tcg cgc gca cgg gcc ctt gtc ttt ggc agc gaa atg gcc tca 762 Thr Thr Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met Ala Ser 170 175 180 185 gcc atc tgt gag gtc cat gcc agc ctg gac ccc tcg ctc agc ctc ttc 810 Ala Ile Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu Ser Leu Phe 190 195 200 tgc tct ggc tcc tgg gag ccc ggt gcg gtg cct cca agc aca gaa cac 858 Cys Ser Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser Thr Glu His 205 210 215 ctg gac cct ctg ctg aaa gat gct ccc aag cac ctt ccc agt tgc cct 906 Leu Asp Pro Leu Leu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro 220 225 230 gac aag ggc ttc aca gat aaa ctg ttc tac atc tac aca tcc ggc acc 954 Asp Lys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 235 240 245 aca ggg ctg ccc aag gcc gcc atc gtg gtg cac agc agg tat tac cgc 1002 Thr Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 250 255 260 265 atg gct gcc ctg gtg tac tat gga ttc cgc atg cgg ccc aac gac atc 1050 Met Ala Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asn Asp Ile 270 275 280 gtc tat gac tgc ctc ccc ctc tac cac tca gca gga aac atc gtg gga 1098 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly 285 290 295 atc ggc cag tgc ctg ctg cat ggc atg acg gtg gtg att cgg aag aag 1146 Ile Gly Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys 300 305 310 ttc tca gcc tcc cgg ttc tgg gac gat tgt atc aag tac aac tgc acg 1194 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr 315 320 325 att gtg cag tac att ggt gaa ctg tgc cgc tac ctc ctg aac cag cca 1242 Ile Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro 330 335 340 345 ccg cgg gag gca gaa aac cag cac cag gtt cgc atg gca cta ggc aat 1290 Pro Arg Glu Ala Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn 350 355 360 ggc ctc cgg cag tcc atc tgg acc aac ttt tcc agc cgc ttc cac ata 1338 Gly Leu Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile 365 370 375 ccc cag gtg gct gag ttc tac ggg gcc aca gag tgc aac tgt agc ctg 1386 Pro Gln Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu 380 385 390 ggc aac ttc gac agc cag gtg ggg gcc tgt ggt ttc aat agc cgc atc 1434 Gly Asn Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile 395 400 405 ctg tcc ttc gtg tac ccc atc cgg ttg gta cgt gtc aac gag gac acc 1482 Leu Ser Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr 410 415 420 425 atg gag ctg atc cgg ggg ccc gac ggc gtc tgc att ccc tgc cag cca 1530 Met Glu Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro 430 435 440 ggt gag ccg ggc cag ctg gtg ggc cgc atc atc cag aaa gac ccc ctg 1578 Gly Glu Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu 445 450 455 cgc cgc ttc gat ggc tac ctc aac cag ggc gcc aac aac aag aag att 1626 Arg Arg Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 460 465 470 gcc aag gat gtc ttc aag aag ggg gac cag gcc tac ctt act ggt gat 1674 Ala Lys Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 475 480 485 gtg ctg gtg atg gac gag ctg ggc tac ctg tac ttc cga gac cgc act 1722 Val Leu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 490 495 500 505 ggg gac acg ttc cgc tgg aaa ggt gag aac gtg tcc acc acc gag gtg 1770 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 510 515 520 gaa ggc aca ctc agc cgc ctg ctg gac atg gct gac gtg gcc gtg tat 1818 Glu Gly Thr Leu Ser Arg Leu Leu Asp Met Ala Asp Val Ala Val Tyr 525 530 535 ggt gtc gag gtg cca gga acc gag ggc cgg gcc gga atg gct gct gtg 1866 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val 540 545 550 gcc agc ccc act ggc aac tgt gac ctg gag cgc ttt gct cag gtc ttg 1914 Ala Ser Pro Thr Gly Asn Cys Asp Leu Glu Arg Phe Ala Gln Val Leu 555 560 565 gag aag gaa ctg ccc ctg tat gcg cgc ccc atc ttc ctg cgc ctc ctg 1962 Glu Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu 570 575 580 585 cct gag ctg cac aaa aca gga acc tac aag ttc cag aag aca gag cta 2010 Pro Glu Leu His Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu 590 595 600 cgg aag gag ggc ttt gac ccg gct att gtg aaa gac ccg ctg ttc tat 2058 Arg Lys Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr 605 610 615 cta gat gcc cag aag ggc cgc tac gtc ccg ctg gac caa gag gcc tac 2106 Leu Asp Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr 620 625 630 agc cgc atc cag gca ggc gag gag aag ctg tgattccccc catccctctg 2156 Ser Arg Ile Gln Ala Gly Glu Glu Lys Leu 635 640 agggccggcg gatgctggat ccggagcccc aggttccgcc ccagagcggt cctggacaag 2216 gccagaccaa agcaagcagg gcctggcacc tccatcctga ggtgctgccc ctccatccaa 2276 aactgccaag tgactcattg ccttcccaac ccttccagag gctttctgtg aaagtctcat 2336 gtccaagttc cgtcttctgg gctgggcagg ccctctggtt cccaggctga gactgacggg 2396 ttttctcagg atgatgtctt gggtgagggt agggagagga caaggggtca ccgagccctt 2456 cccagagagc agggagctta taaatggaac cagagcagaa gtccccagac tcaggaagtc 2516 aacagagtgg gcagggacag tggtagcatc catctggtgg ccaaagagaa tcgtagcccc 2576 agagctgccc aagttcactg ggctccaccc ccacctccag gaggggagga gaggacctga 2636 catctgtagg tggcccctga tgccccatct acagcaggag gtcaggacca cgcccctggc 2696 ctctccccac tcccccatcc tcctccctgg gtggctgcct gattatccct caggcagggc 2756 ctctcagtcc ttgtgggtct gtgtcacctc catctcagtc ttggcctggc tatgagggga 2816 ggaggaatgg gagagggggc tcaggggcca ataaactctg ccttgagtcc tcctaaaaaa 2876 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa agggcggccg c 2917 27 643 PRT Homo sapiens 27 Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215 220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 28 1941 DNA Homo sapiens 28 atgcgggctc cgggtgcggg cgcggcctcg gtggtctcgc tggcgctgtt gtggctgctg 60 gggctgccgt ggacctggag cgcggcagcg gcgctcggcg tgtacgtggg cagcggcggc 120 tggcgcttcc tgcgcatcgt ctgcaagacc gcgaggcgag acctcttcgg tctctctgtg 180 ctgatccgcg tgcgcctgga gctgcggcgg caccagcgtg ccggccacac catcccgcgc 240 atctttcagg cggtagtgca gcgacagccc gagcgcctgg cgctggtgga tgccgggacc 300 ggcgagtgct ggacctttgc gcagctggac gcctactcca atgcggtagc caacctcttc 360 cgccagctgg gcttcgcgcc gggcgacgtg gtggccatct tcctggaggg ccggccggag 420 ttcgtggggc tgtggctggg cctggccaag gcgggcatgg aggccgcgct gctcaacgtg 480 aacctgcggc gcgagcccct ggccttctgc ctgggcacct cgggcgctaa ggccctgatc 540 tttggaggag aaatggtggc ggcggtggcc gaagtgagcg ggcatctggg gaaaagtttg 600 atcaagttct gctctggaga cttggggccc gagggcatct tgccggacac ccacctcctg 660 gacccgctgc tgaaggaggc ctctactgcc cccttggcac agatccccag caagggcatg 720 gacgatcgtc ttttctacat ctacacgtcg gggaccaccg ggctgcccaa ggctgccatt 780 gtcgtgcaca gcaggtacta ccgcatggca gccttcggcc accacgccta ccgcatgcag 840 gcggctgacg tgctctatga ctgcctgccc ctgtaccact cggcaggaaa catcatcggc 900 gtggggcagt gtctcatcta tgggctgaca gtcgtcctcc gcaagaaatt ctcggccagc 960 cgcttctggg acgactgcat caagtacaac tgcacggtgg ttcagtacat cggggagatc 1020 tgccgctacc tgctgaagca gccggtgcgc gaggcggaga ggcgacaccg cgtgcgcctg 1080 gcggtgggga acgggctgcg tcctgccatc tgggaggagt tcacggagcg cttcggcgta 1140 cgccaaatcg gggagttcta cggcgccacc gagtgcaact gcagcattgc caacatggac 1200 ggcaaggtcg gctcctgtgg tttcaacagc cgcatcctgc cccacgtgta ccccatccgg 1260 ctggtgaagg tcaatgagga cacaatggag ctgctgcggg atgcccaggg cctctgcatc 1320 ccctgccagg ccggggagcc tggcctcctt gtgggtcaga tcaaccaaca ggacccgctg 1380 cgccgcttcg atggctatgt cagcgagagc gccaccagca agaagatcgc ccacagcgtc 1440 ttcagcaagg gcgacagcgc ctacctctca ggtgacgtgc tagtgatgga tgagctgggc 1500 tacatgtact tccgggaccg tagcggggac accttccgct ggcgagggga gaacgtctcc 1560 accaccgagg tggagggcgt gctgagccgc ctgctgggcc agacagacgt ggccgtctat 1620 ggggtggctg ttccaggagt ggagggtaag gcagggatgg cggccgtcgc agacccccac 1680 agcctgctgg accccaacgc gatataccag gagctgcaga aggtgctggc accctatgcc 1740 cggcccatct tcctgcgcct cctgccccag gtggacacca caggcacctt caagatccag 1800 aagacgaggc tgcagcgaga gggctttgac ccacgccaga cctcagaccg gctcttcttc 1860 ctggacctga agcagggcca ctacctgccc ttaaatgagg cagtctacac tcgcatctgc 1920 tcgggcgcct tcgccctctg a 1941 29 1938 DNA Mus musculus 29 atgcgggctc ctggagcagg aacagcctct gtggcctcac tggcgctgct ttggtttctg 60 ggacttccgt ggacctggag cgcggcggcg gcgttctgtg tgtacgtggg tggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacg gcgaggcgag acctctttgg cctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacga caccggcgag caggagacac gatcccgtgc 240 atcttccagg ctgtggcccg gcgacaacca gagcgcctgg cactggtgga cgccagtagt 300 ggtatatgct ggaccttcgc acagctggac acctactcca atgctgtagc caacctgttc 360 cgccagctgg gctttgcacc aggcgatgtg gtggctgtgt tcctggaggg ccggccggag 420 ttcgtgggac tgtggctggg cctggccaag gccggtgtgg tggctgctct tctcaatgtc 480 aacctgaggc gggagcccct ggccttctgc ctgggcacat cagctgccaa ggccctcatt 540 tatggcgggg agatggcagc ggcggtggcg gaggtgagcg agcagctggg gaagagcctc 600 ctcaagttct gctctggaga tctggggcct gagagcatcc tgcctgacac gcagctcctg 660 gaccccatgc ttgctgaggc gcccaccaca cccctggcac aagccccagg caagggcatg 720 gatgatcggc tgttttacat ctatacttct gggaccaccg ggcttcctaa ggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgct gcctttggcc accattccta cagcatgcgt 840 gccgccgatg tgctctatga ctgcctgcca ctctaccact ctgcagggaa catcatgggt 900 gtggggcagt gcgtcatcta cgggttgacg gtggtactgc gcaagaagtt ctccgccagc 960 cgcttctggg atgactgtgt caagtacaat tgcacggtag tgcagtacat aggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgc gacgtggagc agcgacaccg cgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatc tgggaggagt tcacgcagcg cttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctacc gagtgcaact gcagcattgc caacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagc cgtatcctca cgcatgtgta ccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggag ccactgcggg actccgaggg cctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctc gtgggccaga tcaaccagca ggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagt gccaccaaca agaagattgc ccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctca ggtgacgtgc tagtgatgga cgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggac accttccgct ggcgcgggga gaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgc ctactgggcc agacggacgt ggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaa gctggcatgg cagccatcgc agatccccac 1680 agccagttgg accctaactc aatgtaccag gaattacaga aggttcttgc atcctatgct 1740 cggcccatct tcctgcgtct tctgccccag gtggatacca caggcacctt caagatccag 1800 aagacccggc tgcagcgtga aggctttgac ccccgtcaga cctcagacag gctcttcttt 1860 ctagacctga agcagggacg ctatgtaccc ctggatgaga gagtccatgc ccgcatttgt 1920 gcaggcgact tctcactc 1938 30 1896 DNA Homo sapiens 30 ctgttctcca agctggtgct gaaactgccc tggacccagg tgggattctc cctgttgttc 60 ctctacttgg gatctggcgg ctggcgcttc atccgggtct tcatcaagac catcaggcgc 120 gatatctttg gcggcctggt cctcctgaag gtgaaggcaa aggtgcgaca gtgcctgcag 180 gagcggcgga cagtgcccat tttgtttgcc tctaccgttc ggcgccaccc cgacaagacg 240 gccctgatct tcgagggcac agatacccac tggaccttcc gccagctgga tgagtactca 300 agcagtgtag ccaacttcct gcaggcccgg ggcctggcct cgggcgatgt ggctgccatc 360 ttcatggaga accgcaatga gttcgtgggc ctatggctgg gcatggccaa gctcggtgtg 420 gaggcagccc tcatcaacac caacctgcgg cgggatgctc tgctccactg cctcaccacc 480 tcgcgcgcac gggcccttgt ctttggcagc gaaatggcct cagccatctg tgaggtccat 540 gccagcctgg acccctcgct cagcctcttc tgctctggct cctgggagcc cggtgcggtg 600 cctccaagca cagaacacct ggaccctctg ctgaaagatg ctcccaagca ccttcccagt 660 tgccctgaca agggcttcac agataaactg ttctacatct acacatccgg caccacaggg 720 ctgcccaagg ccgccatcgt ggtgcacagc aggtattacc gcatggctgc cctggtgtac 780 tatggattcc gcatgcggcc caacgacatc gtctatgact gcctccccct ctaccactca 840 gcaggaaaca tcgtgggaat cggccagtgc ctgctgcatg gcatgacggt ggtgattcgg 900 aagaagttct cagcctcccg gttctgggac gattgtatca agtacaactg cacgattgtg 960 cagtacattg gtgaactgtg ccgctacctc ctgaaccagc caccgcggga ggcagaaaac 1020 cagcaccagg ttcgcatggc actaggcaat ggcctccggc agtccatctg gaccaacttt 1080 tccagccgct tccacatacc ccaggtggct gagttctacg gggccacaga gtgcaactgt 1140 agcctgggca acttcgacag ccaggtgggg gcctgtggtt tcaatagccg catcctgtcc 1200 ttcgtgtacc ccatccggtt ggtacgtgtc aacgaggaca ccatggagct gatccggggg 1260 cccgacggcg tctgcattcc ctgccagcca ggtgagccgg gccagctggt gggccgcatc 1320 atccagaaag accccctgcg ccgcttcgat ggctacctca accagggcgc caacaacaag 1380 aagattgcca aggatgtctt caagaagggg gaccaggcct accttactgg tgatgtgctg 1440 gtgatggacg agctgggcta cctgtacttc cgagaccgca ctggggacac gttccgctgg 1500 aaaggtgaga acgtgtccac caccgaggtg gaaggcacac tcagccgcct gctggacatg 1560 gctgacgtgg ccgtgtatgg tgtcgaggtg ccaggaaccg agggccgggc cggaatggct 1620 gctgtggcca gccccactgg caactgtgac ctggagcgct ttgctcaggt cttggagaag 1680 gaactgcccc tgtatgcgcg ccccatcttc ctgcgcctcc tgcctgagct gcacaaaaca 1740 ggaacctaca agttccagaa gacagagcta cggaaggagg gctttgaccc ggctattgtg 1800 aaagacccgc tgttctatct agatgcccag aagggccgct acgtcccgct ggaccaagag 1860 gcctacagcc gcatccaggc aggcgaggag aagctg 1896 31 1896 DNA Mus musculus 31 cttgggtcca agctagtgct gaagctgccc tggacccagg tgggattctc cctgttgctc 60 ctgtacttgg ggtctggtgg ctggcgtttc atccgggtct tcatcaagac ggtcaggaga 120 gatatctttg gtggcatggt gctcctgaag gtgaagacca aggtgcgacg gtaccttcag 180 gagcggaaga cggtgcccct gctgtttgct tcaatggtac agcgccaccc ggacaagaca 240 gccctgattt tcgagggcac agacactcac tggaccttcc gccagctgga tgagtactcc 300 agtagtgtgg ccaacttcct gcaggcccgg ggcctggcct caggcaatgt agttgccctc 360 tttatggaaa accgcaatga gtttgtgggt ctgtggctag gcatggccaa gctgggcgtg 420 gaggcggctc tcatcaacac caaccttagg cgggatgccc tgcgccactg tcttgacacc 480 tcaaaggcac gagctctcat ctttggcagt gagatggcct cagctatctg tgagatccat 540 gctagcctgg agcccacact cagcctcttc tgctctggat cctgggagcc cagcacagtg 600 cccgtcagca cagagcatct ggaccctctt ctggaagatg ccccgaagca cctgcccagt 660 cacccagaca agggttttac agataagctc ttctacatct acacatcggg caccacgggg 720 ctacccaaag ctgccattgt ggtgcacagc aggtattatc gtatggcttc cctggtgtac 780 tatggattcc gcatgcggcc tgatgacatt gtctatgact gcctccccct ctaccactca 840 agcaggaaac atcgtgggga ttggcagtgc ttactccacg gcatgactgt ggtgatccgg 900 aagaagttct cagcctcccg gttctgggat gattgtatca agtacaactg cacagtggta 960 cagtacattg gcgagctctg ccgctacctc ctgaaccagc caccccgtga ggctgagtct 1020 cggcacaagg tgcgcatggc actgggcaac ggtctccggc agtccatctg gaccgacttc 1080 tccagccgtt tccacatccc ccaggtggct gagttctatg gggccactga atgcaactgt 1140 agcctgggca actttgacag ccgggtgggg gcctgtggct tcaatagccg catcctgtcc 1200 tttgtgtacc ctatccgttt ggtacgtgtc aatgaggata ccatggaact gatccgggga 1260 cccgatggag tctgcattcc ctgtcaacca ggtcagccag gccagctggt gggtcgcatc 1320 atccagcagg accctctgcg ccgtttcgac gggtacctca accagggtgc caacaacaag 1380 aagattgcta atgatgtctt caagaagggg gaccaagcct acctcactgg tgacgtcctg 1440 gtgatggatg agctgggtta cctgtacttc cgagatcgca ctggggacac gttccgctgg 1500 aaaggggaga atgtatctac cactgaggtg gagggcacac tcagccgcct gcttcatatg 1560 gcagatgtgg cagtttatgg tgttgaggtg ccaggaactg aaggccgagc aggaatggct 1620 gccgttgcaa gtcccatcag caactgtgac ctggagagct ttgcacagac cttgaaaaag 1680 gagctgcctc tgtatgcccg ccccatcttc ctgcgcttct tgcctgagct gcacaagaca 1740 gggaccttca agttccagaa gacagagttg cggaaggagg gctttgaccc atctgttgtg 1800 aaagacccgc tgttctatct ggatgctcgg aagggctgct acgttgcact ggaccaggag 1860 gcctataccc gcatccaggc aggcgaggag aagctg 1896 32 646 PRT Homo sapiens 32 Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 33 646 PRT Mus musculus 33 Met Arg Ala Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly Gly Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala Val Ala Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly Arg Tyr Val Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 34 632 PRT Homo sapiens 34 Leu Phe Ser Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 Ser Leu Leu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 Val Phe Ile Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu 35 40 45 Leu Lys Val Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr 50 55 60 Val Pro Ile Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr 65 70 75 80 Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105 110 Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe 115 120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu 130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr 145 150 155 160 Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile 165 170 175 Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp 195 200 205 Pro Leu Leu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly 275 280 285 Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val 305 310 315 320 Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335 Glu Ala Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu 340 345 350 Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln 355 360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn 370 375 380 Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg Leu Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Thr Gly Asn Cys Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys 545 550 555 560 Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu 565 570 575 Leu His Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585 590 Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp 595 600 605 Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg 610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 35 632 PRT Mus musculus 35 Leu Gly Ser Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 Ser Leu Leu Leu Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 Val Phe Ile Lys Thr Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu 35 40 45 Leu Lys Val Lys Thr Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr 50 55 60 Val Pro Leu Leu Phe Ala Ser Met Val Gln Arg His Pro Asp Lys Thr 65 70 75 80 Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105 110 Ala Ser Gly Asn Val Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe 115 120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu 130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr 145 150 155 160 Ser Lys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile 165 170 175 Cys Glu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His Leu Asp 195 200 205 Pro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly Asp Trp 275 280 285 Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val 305 310 315 320 Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335 Glu Ala Glu Ser Arg His Lys Val Arg Met Ala Leu Gly Asn Gly Leu 340 345 350 Arg Gln Ser Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln 355 360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn 370 375 380 Phe Asp Ser Arg Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys 545 550 555 560 Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu 565 570 575 Leu His Lys Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585 590 Glu Gly Phe Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp 595 600 605 Ala Arg Lys Gly Cys Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg 610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 36 2885 DNA Homo sapiens 36 aacggcaagt aagcgcaacg caattaatgt gagtagctca ctcattaggc accccaggct 60 ttacacttta tgcttccggg ctcgtatgtt gtgtggaatt gtgagcggat accaatttca 120 cacaggaacc agctatgaca tgattacgaa tttaatacga ctcactatag ggaatttggc 180 cctcgaggcc aagaattcgg cacgaggggt gctgagcccc tgcgcggttt ctggtgcgta 240 gagactgtaa atcgctgcgc ttctcagtca tcatcatccc agcttttccc ggctcgaatt 300 cagcctccaa ctcaagctcg cgggaaagac tacctgagag gagaaaagct tctgtccctg 360 gaccttcttc tgagggtgga gtcggaggct ccctgctttc cagccgccca gtgacccaag 420 cttaatcttc agcaccactt ggggcgacct tttcggtgca aacctacgat tctgtttctc 480 aggattcctc cccatcccgc ttcgccccgg aaaagctgac aagaacttca ggtgtaagcc 540 ctgagtagtg aggatctgcg gtctccgtgg agagctgtgc ctggaagaga aggacgctgg 600 tgggggctga gatcagagct gtcttctggc ccagttgccc ccatgcttct gtcatggcta 660 acagttctag gggctggaat ggtcgtcctg cacttcttgc agaaactcct gttcccttac 720 ttttgggatg acttctggtt cgtgttgaag gtggtgctca ttataattcg gctgaagaag 780 tatgaaaaga gaggggagct ggtgactgtg ctggataaat tcttgagtca tgccaaaaga 840 caacctcgga aacctttcat catctatgag ggagacatct acacctatca ggatgtagac 900 aaaaggagca gcagagtggc ccatgtcttc ctgaaccatt cctctctgaa aaagggggac 960 acggtggctc tgctgatgag caatgagccg gacttcgttc acgtgtggtt cggcctcgcc 1020 aagctgggct gcgtggtggc ctttctcaac accaacattc gctccaactc cctcctgaat 1080 tgcatccgcg cctgtgggcc cagagcccta gtggtgggcg cagatttgct tggaacggta 1140 gaagaaatcc ttccaagcct ctcagaaaat atcagtgttt gggggatgaa agattctgtt 1200 ccacaaggtg taatttcact caaagaaaaa ctgagcacct cacctgatga gcccgtgcca 1260 cgcagccacc atgttgtctc actcctcaag tctacttgtc tttacatttt tacctctgga 1320 acaacaggtc taccaaaagc agctgtgatt agtcagctgc aggttttaag gggttctgct 1380 gtcctgtggg cttttggttg tactgctcat gacattgttt atataaccct tcctctgtat 1440 catagttcag cagctatcct gggaatttct ggatgtgttg agttgggtgc cacttgtgtg 1500 ttaaagaaga aattttcagc aagccagttt tggagtgact gcaagaagta tgatgtgact 1560 gtgtttcagt atattggaga actttgtcgc tacctttgca aacaatctaa gagagaagga 1620 gaaaaggatc ataaggtgcg tttggcaatt ggaaatggca tacggagtga tgtatggaga 1680 gaatttttag acagatttgg aaatataaag gtgtgtgaac tttatgcagc taccgaatca 1740 agcatatctt tcatgaacta cactgggaga attggagcaa ttgggagaac aaatttgttt 1800 tacaaacttc tttccacttt tgacttaata aagtatgact ttcagaaaga tgaacccatg 1860 agaaatgagc agggttggtg tattcatgtg aaaaaaggag aacctggact tctcatttct 1920 cgagtgaatg caaaaaatcc cttctttggc tatgctgggc cttataagca cacaaaagac 1980 aaattgcttt gtgatgtttt taagaaggga gatgtttacc ttaatactgg agacttaata 2040 gtccaggatc aggacaattt cctttatttt tgggaccgta ctggagacac tttcagatgg 2100 aaaggagaaa atgtcgcaac cactgaggtt gctgatgtta ttggaatgtt ggatttcata 2160 caggaagcaa acgtctatgg tgtggctata tcaggttatg aaggaagagc aggaatggct 2220 tctattattt taaaaccaaa tacatcttta gatttggaaa aagtttatga acaagttgta 2280 acatttctac cagcttatgc ttgtccacga tttttaagaa ttcaggaaaa aatggaagca 2340 acaggaacat tcaaactatt gaagcatcag ttggtggaag atggatttaa tccactgaaa 2400 atttctgaac cactttactt catggataac ttgaaaaagt cttatgttct actgaccagg 2460 gaactttatg atcaaataat gttaggggaa ataaaacttt aagattttta tatctagaac 2520 tttcatatgc tttcttagga agagtgagag gggggtatat gattctttat gaaatgggga 2580 aagggagcta acattaatta tgcatgtact atatttcctt aatatgagag ataatttttt 2640 aattgcataa gaattttaat ttcttttaat tgatataaac attagttgat tattcttttt 2700 atctatttgg agattcagtg cataactaag tattttcctt aatactaaag attttaaata 2760 ataaatagtg gctagcggtt tggacaatca ctaaaaatgt actttctaat aagtaaaatt 2820 tctaattttg aataaaagat taaattttac tgaaaaaaaa aaaaaaaaaa aaaattggcg 2880 gccgc 2885 37 619 PRT Homo sapiens 37 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val Val Leu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu Ser His Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val Ala His Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val Ala Leu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe Gly Leu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn Ile Arg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro Arg Ala Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu Glu Ile Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met Lys Asp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu Ser Thr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val Ser Leu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val Leu Arg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 Asp Ile Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270 Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280 285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290 295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys 305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg Leu Ala Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe Leu Asp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala Thr Glu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala Ile Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly Leu Leu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510 Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520 525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530 535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile 545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu Lys His Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu Thr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 610 615 38 646 PRT Homo sapiens 38 Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 39 632 PRT Homo sapiens 39 Leu Phe Ser Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 Ser Leu Leu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 Val Phe Ile Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu 35 40 45 Leu Lys Val Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr 50 55 60 Val Pro Ile Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr 65 70 75 80 Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105 110 Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe 115 120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu 130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr 145 150 155 160 Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile 165 170 175 Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp 195 200 205 Pro Leu Leu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly 275 280 285 Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val 305 310 315 320 Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335 Glu Ala Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu 340 345 350 Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln 355 360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn 370 375 380 Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg Leu Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Thr Gly Asn Cys Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys 545 550 555 560 Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu 565 570 575 Leu His Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585 590 Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp 595 600 605 Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg 610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 40 619 PRT Homo sapiens 40 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val Val Leu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu Ser His Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val Ala His Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val Ala Leu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe Gly Leu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn Ile Arg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro Arg Ala Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu Glu Ile Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met Lys Asp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu Ser Thr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val Ser Leu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val Leu Arg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 Asp Ile Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270 Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280 285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290 295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys 305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg Leu Ala Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe Leu Asp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala Thr Glu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala Ile Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly Leu Leu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510 Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520 525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530 535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile 545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu Lys His Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu Thr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 610 615 41 643 PRT Homo sapiens 41 Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215 220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 42 643 PRT Mus musculus VARIANT (1)...(643) Xaa = Any Amino Acid 42 Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Xaa Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 Ala Ser Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120 125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Xaa 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys Ala Arg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Ile His Ala 180 185 190 Ser Leu Gly Pro Thr Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu Asp Pro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro Ser His Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser Arg Lys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350 His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu His Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610 615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 43 646 PRT Homo sapiens 43 Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 44 2710 DNA Mus musculus 44 atgctgcttg gagcctctct ggtgggggcg ctacttgggt ccaagctagt gctgaagctg 60 ccctggaccc aggtgggatt ctccctgttg ctcctgtact tggggtctgg tggctggcgt 120 ttcatccggg tcttcatcaa gacggtcagg agagatatct ttggtggcat ggtgctcctg 180 aaggtgaaga ccaaggtgcg acggtacctt caggagcgga agacggtgcc cctgctgttt 240 gcttcaatgg tacagcgcca cccggacaag acagccctga ttttcgaggg cacagacact 300 cactggacct tccgccagct ggatgagtac tccagtagtg tggccaactt cctgcaggcc 360 cggggcctgg cctcaggcaa tgtagttgcc ctctttatgg aaaaccgcaa tgagtttgtg 420 ggtctgtggc taggcatggc caagctgggc gtggaggcgg ctctcatcaa caccaacctt 480 aggcgggatg ccctgcgcca ctgtcttgac acctcaaagg cacgagctct catctttggc 540 agtgagatgg cctcagctat ctgtgagatc catgctagcc tggagcccac actcagcctc 600 ttctgctctg gatcctggga gcccagcaca gtgcccgtca gcacagagca tctggaccct 660 cttctggaag atgccccgaa gcacctgccc agtcacccag acaagggttt tacagataag 720 ctcttctaca tctacacatc gggcaccacg gggctaccca aagctgccat tgtggtgcac 780 agcaggtatt atcgtatggc ttccctggtg tactatggat tccgcatgcg gcctgatgac 840 attgtctatg actgcctccc cctctaccac tcaagcagga aacatcgtgg ggattggcag 900 tgcttactcc acggcatgac tgtggtgatc cggaagaagt tctcagcctc ccggttctgg 960 gatgattgta tcaagtacaa ctgcacagtg gtacagtaca ttggcgagct ctgccgctac 1020 ctcctgaacc agccaccccg tgaggctgag tctcggcaca aggtgcgcat ggcactgggc 1080 aacggtctcc ggcagtccat ctggaccgac ttctccagcc gtttccacat cccccaggtg 1140 gctgagttct atggggccac tgaatgcaac tgtagcctgg gcaactttga cagccgggtg 1200 ggggcctgtg gcttcaatag ccgcatcctg tcctttgtgt accctatccg tttggtacgt 1260 gtcaatgagg ataccatgga actgatccgg ggacccgatg gagtctgcat tccctgtcaa 1320 ccaggtcagc caggccagct ggtgggtcgc atcatccagc aggaccctct gcgccgtttc 1380 gacgggtacc tcaaccaggg tgccaacaac aagaagattg ctaatgatgt cttcaagaag 1440 ggggaccaag cctacctcac tggtgacgtc ctggtgatgg atgagctggg ttacctgtac 1500 ttccgagatc gcactgggga cacgttccgc tggaaagggg agaatgtatc taccactgag 1560 gtggagggca cactcagccg cctgcttcat atggcagatg tggcagttta tggtgttgag 1620 gtgccaggaa ctgaaggccg agcaggaatg gctgccgttg caagtcccat cagcaactgt 1680 gacctggaga gctttgcaca gaccttgaaa aaggagctgc ctctgtatgc ccgccccatc 1740 ttcctgcgct tcttgcctga gctgcacaag acagggacct tcaagttcca gaagacagag 1800 ttgcggaagg agggctttga cccatctgtt gtgaaagacc cgctgttcta tctggatgct 1860 cggaagggct gctacgttgc actggaccag gaggcctata cccgcatcca ggcaggcgag 1920 gagaagctgt gatttccccc tacatccctc tgagggccag aagatgctgg attcagagcc 1980 ctagcgtcca ccccagaggg tcctgggcaa tgccagacca aagctagcag ggcccgcacc 2040 tccgccccta ggtgctgatc tcccctctcc caaactgcca agtgactcac tgccgcttcc 2100 ccgaccctcc agaggctttc tgtgaaagtc tcatccaagc tgtgtcttct ggtccaggcg 2160 tggcccctgg ccccagggtt tctgataggc tcctttagga tggtatcttg ggtccagcgg 2220 gccagggtgt gggagaggag tcactaagat ccctccaatc agaagggagc ttacaaagga 2280 accaaggcaa agcctgtaga ctcaggaagc taagtggcca gagactatag tggccagtca 2340 tcccatgtcc acagaggatc ttggtccaga gctgccaaag tgtcacctct ccctgcctgc 2400 acctctgggg aaaagaggac agcatgtggc cactgggcac ctgtctcaag aagtcaggat 2460 cacacactca gtccttgttt ctccaggttc ccttgttctt gtctcgggga gggagggacg 2520 agtgtcctgt ctgtccttcc tgcctgtctg tgagtctgtg ttgcttctcc atctgtccta 2580 gcctgagtgt gggtggaaca ggcatgagga gagtgtggct caggggccaa taaactctgc 2640 cttgactcct cttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaa 2710 45 643 PRT Mus musculus 45 Met Leu Leu Gly Ala Ser Leu Val Gly Ala Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Leu Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 Ala Ser Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120 125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys Ala Arg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Ile His Ala 180 185 190 Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu Asp Pro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro Ser His Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser Arg Lys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350 His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu His Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610 615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 46 3694 DNA Homo sapiens 46 tcgacccacg gcgtccggga ccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtcc aggagtctgc agaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcct gcctgagctt ctgggagact gaaggcacgg cttgcagctt caggatgcgg 180 gctccgggtg cgggcgcggc ctcggtggtc tcgctggcgc tgttgtggct gctggggctg 240 ccgtggacct ggagcgcggc agcggcgctc ggcgtgtacg tgggcagcgg cggctggcgc 300 ttcctgcgca tcgtctgcaa gaccgcgagg cgagacctct tcggtctctc tgtgctgatc 360 cgcgtgcgcc tggagctgcg gcggcaccag cgtgccggcc acaccatccc gcgcatcttt 420 caggcggtag tgcagcgaca gcccgagcgc ctggcgctgg tggatgccgg gaccggcgag 480 tgctggacct ttgcgcagct ggacgcctac tccaatgcgg tagccaacct cttccgccag 540 ctgggcttcg cgccgggcga cgtggtggcc atcttcctgg agggccggcc ggagttcgtg 600 gggctgtggc tgggcctggc caaggcgggc atggaggccg cgctgctcaa cgtgaacctg 660 cggcgcgagc ccctggcctt ctgcctgggc acctcgggcg ctaaggccct gatctttgga 720 ggagaaatgg tggcggcggt ggccgaagtg agcgggcatc tggggaaaag tttgatcaag 780 ttctgctctg gagacttggg gcccgagggc atcttgccgg acacccacct cctggacccg 840 ctgctgaagg aggcctctac tgcccccttg gcacagatcc ccagcaaggg catggacgat 900 cgtcttttct acatctacac gtcggggacc accgggctgc ccaaggctgc cattgtcgtg 960 cacagcaggt actaccgcat ggcagccttc ggccaccacg cctaccgcat gcaggcggct 1020 gacgtgctct atgactgcct gcccctgtac cactcggcag gaaacatcat cggcgtgggg 1080 cagtgtctca tctatgggct gacagtcgtc ctccgcaaga aattctcggc cagccgcttc 1140 tgggacgact gcatcaagta caactgcacg gtggttcagt acatcgggga gatctgccgc 1200 tacctgctga agcagccggt gcgcgaggcg gagaggcgac accgcgtgcg cctggcggtg 1260 gggaacgggc tgcgtcctgc catctgggag gagttcacgg agcgcttcgg cgtacgccaa 1320 atcggggagt tctacggcgc caccgagtgc aactgcagca ttgccaacat ggacggcaag 1380 gtcggctcct gtggtttcaa cagccgcatc ctgccccacg tgtaccccat ccggctggtg 1440 aaggtcaatg aggacacaat ggagctgctg cgggatgccc agggcctctg catcccctgc 1500 caggccgggg agcctggcct ccttgtgggt cagatcaacc aacaggaccc gctgcgccgc 1560 ttcgatggct atgtcagcga gagcgccacc agcaagaaga tcgcccacag cgtcttcagc 1620 aagggcgaca gcgcctacct ctcaggtgac gtgctagtga tggatgagct gggctacatg 1680 tacttccggg accgtagcgg ggacaccttc cgctggcgag gggagaacgt ctccaccacc 1740 gaggtggagg gcgtgctgag ccgcctgctg ggccagacag acgtggccgt ctatggggtg 1800 gctgttccag gagtggaggg taaggcaggg atggcggccg tcgcagaccc ccacagcctg 1860 ctggacccca acgcgatata ccaggagctg cagaaggtgc tggcacccta tgcccggccc 1920 atcttcctgc gcctcctgcc ccaggtggac accacaggca ccttcaagat ccagaagacg 1980 aggctgcagc gagagggctt tgacccacgc cagacctcag accggctctt cttcctggac 2040 ctgaagcagg gccactacct gcccttaaat gaggcagtct acactcgcat ctgctcgggc 2100 gccttcgccc tctgaagctg ttcctctact ggccacaaac tctgggcctg gtgggagagg 2160 ccagcttgag ccagacagcg ctgcccaggg gtggccgcct agtacacacc cacctggccg 2220 agctgtacct ggcacggccc atcctggact gagaaactgg aacctcagag gaacccgtgc 2280 ctctctgctg ccttggtgcc cctgtgtctg cctcctctcc ctgcttttca gcctctgtct 2340 ccttccatcc ctgtccctgt ctggccttaa ctcttccctc tctttctttt ctttctttct 2400 ttcttttttt ttaagataga gtctcactct gctgcccggg ctagagtgca gtggtgggat 2460 ctcggctcac tgcaacctct gcctcctggg gttcaagtga tcctcccacc tcagcctcct 2520 gagtagctgg gattacaggc acccgccacc acgtccagct aatttttata tttttagtag 2580 agacggggtt tcaccatgtt ggtcaggctg gtcttgaact cctgacctca ggtgatccgc 2640 tggcctcggc ctcccagagt gctgggatta taggcgtgag cctctggccc ggcctttcct 2700 ttttcctctc ctctcctgcc gagagtggaa cacacgtgtc ctgggagctg catcttgtgt 2760 agggtccagc tgcttttggg gactgcagga atcatctccc ctgggccctg gactcggact 2820 ggggcctccc cacctccctc tcggctgtgc cttacggagc cccaatccag gcctcctgtg 2880 gctgttgggt tccagatgct gcagctccat gtgacttcca agcaggccct ccgccctccc 2940 tgctgaatgg aggagccggg ggtcccccag gccaactgga aaatctccca ggctaggcca 3000 attgcctttt gcacttcccc gttcctgtca catttcccca gccccacctt cccctcctga 3060 tgccctgaaa gcttccggaa ttgactgtga ccacttggat gtcaccactg tcagcccctg 3120 ccttgatgtc cccatttagc catctccatg gagctcctgc tggagggccc tgaaccctgc 3180 actgcgtggc tgcccagcca gctgcctcct gtcctgggag gaggcctcct gggtgtcctc 3240 atctggtgtg tctactggag ggtcccacag gagaggcagc agaggggtca ggggaggtct 3300 cctgccgggg gttggcctct caagcctcag gggttctagc ctgttgaata taccccacct 3360 ggtgggtggc ccctccgatg tccccactga tggctctgac accgtgttgg tggcgatgtc 3420 ccagacaatc ccaccaggac ggcccagaca tccctactgg cttcgctggt ggctcatctc 3480 gaacatccac gccagccttt ctggggccgg ccacccaggc cgcctgtccg tctgtcctcc 3540 ctccagcagc accccctggc ccctggagtg gtggggccat ggcaagagac accgtggcgt 3600 ctcatgtgaa ctttcctggg cactgtggtt ttatttccta attgatttaa gaaataaacc 3660 tgaagaccgt ctggtgaaaa aaaaaaaaaa aaaa 3694 47 646 PRT Homo sapiens 47 Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 48 2362 DNA Homo sapiens 48 ggaattccaa aaaaaaaaaa tacgactaca cctgctccgg agcccgcggc ggtacctgca 60 gcggaggagc tctgtcttcc ccttcatctc acgcgagccc ggcgtcccgc cgcgtgcgcc 120 ccggcgcagc ccgccagtcc gcccggagcc cgcccagtcg ccgcgctgca cgcccggggt 180 gaaccctctg ccctcgctgg gacagagggc cccgcagccg tcatgctttc cgccatctac 240 acagtcctgg cgggactgct gttcctgccg ctcctggtga acctctgctg cccatacttc 300 ttccaggaca taggctactt cttgaaggtg gccgccgtgg gccggagggt gcgcagctac 360 gggcagcggc ggccggcgcg caccatcctg cgggcgttcc tggagaaagc gcgccagacg 420 ccacacaagc cttttctgct cttccgcgac gagactctca cctacgcgca ggtggaccgg 480 cgcagcaatc aagtggcccg ggcgctgcac gaccacctcg gcctgcgcca gggagactgc 540 gtggcgctcc ttatgggtaa cgagccggcc tacgtgtggc tgtggctggg gctggtgaag 600 ctgggctgtg ccatggcgtg cctcaattac aacatccgcg cgaagtccct gctgcactgc 660 ttccagtgct gcggggcgaa ggtgctgctg gtgtcgccag aactacaagc agctgtcgaa 720 gagatactgc caagccttaa aaaagatgat gtgtccatct attatgtgag cagaacttct 780 aacacagatg ggattgactc tttcctggac aaagtggatg aagtatcaac tgaacctatc 840 ccagagtcat ggaggtctga agtcactttt tccactcctg ccttatacat ttatacttct 900 ggaaccacag gtcttccaaa agcagccatg atcactcatc agcgcatatg gtatggaact 960 ggcctcactt ttgtaagcgg attgaaggca gatgatgtca tctatatcac tctgcccttt 1020 taccacagtg ctgcactact gattggcatt cacggatgta ttgtggctgg tgctactctt 1080 gccttgcgga ctaaattttc agccagccag ttttgggatg actgcagaaa atacaacgtc 1140 actgtcattc agtatatcgg tgaactgctt cggtatttat gcaactcacc acagaaacca 1200 aatgaccgtg atcataaagt gagactggca ctgggaaatg gcttacgagg agatgtgtgg 1260 agacaatttg tcaagagatt tggggacata tgcatctatg agttctatgc tgccactgaa 1320 ggcaatattg gatttatgaa ttatgcgaga aaagttggtg ctgttggaag agtaaactac 1380 ctacagaaaa aaatcataac ttatgacctg attaaatatg atgtggagaa agatgaacct 1440 gtccgagatg aaaatggata ttgcgtcaga gttcccaaag gtgaagttgg acttctggtt 1500 tgcaaaatca cacaacttac accatttaat ggctatgctg gagcaaaggc tcagacagag 1560 aagaaaaaac tgagagatgt ctttaagaaa ggagacctct atttcaacag tggagatctc 1620 ttaatggttg accatgaaaa tttcatctat ttccacgaca gagttggaga tacattccgg 1680 tggaaagggg aaaatgtggc caccactgaa gttgctgata cagttggact ggttgatttt 1740 gtccaagaag taaatgttta tggagtgcat gtgccagatc atgagggtcg cattggcatg 1800 gcctccatca aaatgaaaga aaaccatgaa tttgatggaa agaaactctt tcagcacatt 1860 gctgattacc tacctagtta tgcaaggccc cggtttctaa gaatacagga caccattgag 1920 atcactggaa cttttaaaca ccgcaaaatg accctggtgg aggagggctt taaccctgct 1980 gtcatcaaag atgccttgta tttcttggat gacacagcaa aaatgtatgt gcctatgact 2040 gaggacatct ataatgccat aagtgctaaa accctgaaac tctgaatatt cccaggagga 2100 taactcaaca tttccagaaa gaaactgaat ggacagccac ttgatataat ccaactttaa 2160 tttgattgaa gattgtgagg aaattttgta ggaaatttgc atacccgtaa agggagactt 2220 ttttaaataa cagttgagtc tttgcaagta aaaagattta gagattatta tttttcagtg 2280 tgcacctact gtttgtattt gcaaactgag cttgttggag ggaaggcatt attttttaaa 2340 atacttagta aattaaatga ac 2362 49 620 PRT Homo sapiens 49 Met Leu Ser Ala Ile Tyr Thr Val Leu Ala Gly Leu Leu Phe Leu Pro 1 5 10 15 Leu Leu Val Asn Leu Cys Cys Pro Tyr Phe Phe Gln Asp Ile Gly Tyr 20 25 30 Phe Leu Lys Val Ala Ala Val Gly Arg Arg Val Arg Ser Tyr Gly Gln 35 40 45 Arg Arg Pro Ala Arg Thr Ile Leu Arg Ala Phe Leu Glu Lys Ala Arg 50 55 60 Gln Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp His Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Leu Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Leu Trp Leu Gly Leu Val Lys Leu Gly 115 120 125 Cys Ala Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Val Ser Pro Glu 145 150 155 160 Leu Gln Ala Ala Val Glu Glu Ile Leu Pro Ser Leu Lys Lys Asp Asp 165 170 175 Val Ser Ile Tyr Tyr Val Ser Arg Thr Ser Asn Thr Asp Gly Ile Asp 180 185 190 Ser Phe Leu Asp Lys Val Asp Glu Val Ser Thr Glu Pro Ile Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Ser Thr Pro Ala Leu Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Met Ile Thr His Gln 225 230 235 240 Arg Ile Trp Tyr Gly Thr Gly Leu Thr Phe Val Ser Gly Leu Lys Ala 245 250 255 Asp Asp Val Ile Tyr Ile Thr Leu Pro Phe Tyr His Ser Ala Ala Leu 260 265 270 Leu Ile Gly Ile His Gly Cys Ile Val Ala Gly Ala Thr Leu Ala Leu 275 280 285 Arg Thr Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Ser Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val Arg Leu Ala 325 330 335 Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Gln Phe Val Lys Arg 340 345 350 Phe Gly Asp Ile Cys Ile Tyr Glu Phe Tyr Ala Ala Thr Glu Gly Asn 355 360 365 Ile Gly Phe Met Asn Tyr Ala Arg Lys Val Gly Ala Val Gly Arg Val 370 375 380 Asn Tyr Leu Gln Lys Lys Ile Ile Thr Tyr Asp Leu Ile Lys Tyr Asp 385 390 395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Glu Asn Gly Tyr Cys Val Arg 405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys Ile Thr Gln Leu 420 425 430 Thr Pro Phe Asn Gly Tyr Ala Gly Ala Lys Ala Gln Thr Glu Lys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Leu Tyr Phe Asn Ser Gly 450 455 460 Asp Leu Leu Met Val Asp His Glu Asn Phe Ile Tyr Phe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Thr Val Gly Leu Val Asp Phe Val Gln Glu Val Asn Val 500 505 510 Tyr Gly Val His Val Pro Asp His Glu Gly Arg Ile Gly Met Ala Ser 515 520 525 Ile Lys Met Lys Glu Asn His Glu Phe Asp Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ala Asp Tyr Leu Pro Ser Tyr Ala Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr Phe Lys His Arg Lys Met 565 570 575 Thr Leu Val Glu Glu Gly Phe Asn Pro Ala Val Ile Lys Asp Ala Leu 580 585 590 Tyr Phe Leu Asp Asp Thr Ala Lys Met Tyr Val Pro Met Thr Glu Asp 595 600 605 Ile Tyr Asn Ala Ile Ser Ala Lys Thr Leu Lys Leu 610 615 620 50 1173 DNA Homo sapiens 50 aagttctcgg ctggtcagtt ctgggaagat tgccagcagc acagggtgac ggtgttccag 60 tacattgggg agctgtgccg ataccttgtc aaccagcccc cgagcaaggc agaacgtggc 120 cataaggtcc ggctggcagt gggcagcggg ctgcgcccag atacctggga gcgttttgtg 180 cggcgcttcg ggcccctgca ggtgctggag acatatggac tgacagaggg caacgtggcc 240 accatcaact acacaggaca gcggggcgct gtggggcgtg cttcctggct ttacaagcat 300 atcttcccct tctccttgat tcgctatgat gtcaccacag gagagccaat tcgggacccc 360 caggggcact gtatggccac atctccaggt gagccagggc tgctggtggc cccggtaagc 420 cagcagtccc cattcctggg ctatgctggc gggccagagc tggcccaggg gaagttgcta 480 aaggatgtct tccggcctgg ggatgttttc ttcaacactg gggacctgct ggtctgcgat 540 gaccaaggtt ttctccgctt ccatgatcgt actggagaca ccttcaggtg gaagggggag 600 aatgtggcca caaccgaggt ggcagaggtc ttcgaggccc tagattttct tcaggaggtg 660 aacgtctatg gagtcactgt gccagggcat gaaggcaggg ctggaatggc agccctagtt 720 ctgcgtcccc cccacgcttt ggaccttatg cagctctaca cccacgtgtc tgagaacttg 780 ccaccttatg cccggccccg attcctcagg ctccaggagt ctttggccac cacagagacc 840 ttcaaacagc agaaagttcg gatggcaaat gagggcttcg accccagcac cctgtctgac 900 ccactgtacg ttctggacca ggctgtaggt gcctacctgc ccctcacaac tgcccggtac 960 agcgccctcc tggcaggaaa ccttcgaatc tgagaacttc cacacctgag gcacctgaga 1020 gaggaactct gtggggtggg ggccgttgca ggtgtactgg gctgtcaggg atcttttcta 1080 taccagaact gcggtcacta ttttgtaata aatgtggctg gagctgatcc agctgtctct 1140 gacaaaaaaa aaaaaaaaaa aaagggcggc cgc 1173 51 330 PRT Homo sapiens 51 Lys Phe Ser Ala Gly Gln Phe Trp Glu Asp Cys Gln Gln His Arg Val 1 5 10 15 Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Val Asn Gln 20 25 30 Pro Pro Ser Lys Ala Glu Arg Gly His Lys Val Arg Leu Ala Val Gly 35 40 45 Ser Gly Leu Arg Pro Asp Thr Trp Glu Arg Phe Val Arg Arg Phe Gly 50 55 60 Pro Leu Gln Val Leu Glu Thr Tyr Gly Leu Thr Glu Gly Asn Val Ala 65 70 75 80 Thr Ile Asn Tyr Thr Gly Gln Arg Gly Ala Val Gly Arg Ala Ser Trp 85 90 95 Leu Tyr Lys His Ile Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Thr 100 105 110 Thr Gly Glu Pro Ile Arg Asp Pro Gln Gly His Cys Met Ala Thr Ser 115 120 125 Pro Gly Glu Pro Gly Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro 130 135 140 Phe Leu Gly Tyr Ala Gly Gly Pro Glu Leu Ala Gln Gly Lys Leu Leu 145 150 155 160 Lys Asp Val Phe Arg Pro Gly Asp Val Phe Phe Asn Thr Gly Asp Leu 165 170 175 Leu Val Cys Asp Asp Gln Gly Phe Leu Arg Phe His Asp Arg Thr Gly 180 185 190 Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val Ala 195 200 205 Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu Val Asn Val Tyr Gly 210 215 220 Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met Ala Ala Leu Val 225 230 235 240 Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln Leu Tyr Thr His Val 245 250 255 Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe Leu Arg Leu Gln 260 265 270 Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln Lys Val Arg Met 275 280 285 Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser Asp Pro Leu Tyr Val 290 295 300 Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro Leu Thr Thr Ala Arg Tyr 305 310 315 320 Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile 325 330 52 2907 DNA Homo sapiens 52 cgacccacgc gtccgggcgg gcggggccgg gcggcgggcg gggctggcgg ggcggccggg 60 ccatgcaggg cgcagagccg gctaaaccct gctgagaccc ggctccgtgc gtccaggggc 120 ggctaatgcc cctcacgctg tctacgctgc tgcaaccggg ccgcatctgg acggggcgcc 180 gcgcggcgga gccgacgccg ggccacaatg ctgcttggag cctctctggt gggggtgctg 240 ctgttctcca agctggtgct gaaactgccc tggacccagg tgggattctc cctgttgttc 300 ctctacttgg gatctggcgg ctggcgcttc atccgggtct tcatcaagac catcaggcgc 360 gatatctttg gcggcctggt cctcctgaag gtgaaggcaa aggtgcgaca gtgcctgcag 420 gagcggcgga cagtgcccat tttgtttgcc tctaccgttc ggcgccaccc cgacaagacg 480 gccctgatct tcgagggcac agatacccac tggaccttcc gccagctgga tgagtactca 540 agcagtgtag ccaacttcct gcaggcccgg ggcctggcct cgggcgatgt ggctgccatc 600 ttcatggaga accgcaatga gttcgtgggc ctatggctgg gcatggccaa gctcggtgtg 660 gaggcagccc tcatcaacac caacctgcgg cgggatgctc tgctccactg cctcaccacc 720 tcgcgcgcac gggcccttgt ctttggcagc gaaatggcct cagccatctg tgaggtccat 780 gccagcctgg acccctcgct cagcctcttc tgctctggct cctgggagcc cggtgcggtg 840 cctccaagca cagaacacct ggaccctctg ctgaaagatg ctcccaagca ccttcccagt 900 tgccctgaca agggcttcac agataaactg ttctacatct acacatccgg caccacaggg 960 ctgcccaagg ccgccatcgt ggtgcacagc aggtattacc gcatggctgc cctggtgtac 1020 tatggattcc gcatgcggcc caacgacatc gtctatgact gcctccccct ctaccactca 1080 gcaggaaaca tcgtgggaat cggccagtgc ctgctgcatg gcatgacggt ggtgattcgg 1140 aagaagttct cagcctcccg gttctgggac gattgtatca agtacaactg cacgattgtg 1200 cagtacattg gtgaactgtg ccgctacctc ctgaaccagc caccgcggga ggcagaaaac 1260 cagcaccagg ttcgcatggc actaggcaat ggcctccggc agtccatctg gaccaacttt 1320 tccagccgct tccacatacc ccaggtggct gagttctacg gggccacaga gtgcaactgt 1380 agcctgggca acttcgacag ccaggtgggg gcctgtggtt tcaatagccg catcctgtcc 1440 ttcgtgtacc ccatccggtt ggtacgtgtc aacgaggaca ccatggagct gatccggggg 1500 cccgacggcg tctgcattcc ctgccagcca ggtgagccgg gccagctggt gggccgcatc 1560 atccagaaag accccctgcg ccgcttcgat ggctacctca accagggcgc caacaacaag 1620 aagattgcca aggatgtctt caagaagggg gaccaggcct accttactgg tgatgtgctg 1680 gtgatggacg agctgggcta cctgtacttc cgagaccgca ctggggacac gttccgctgg 1740 aaaggtgaga acgtgtccac caccgaggtg gaaggcacac tcagccgcct gctggacatg 1800 gctgacgtgg ccgtgtatgg tgtcgaggtg ccaggaaccg agggccgggc cggaatggct 1860 gctgtggcca gccccactgg caactgtgac ctggagcgct ttgctcaggt cttggagaag 1920 gaactgcccc tgtatgcgcg ccccatcttc ctgcgcctcc tgcctgagct gcacaaaaca 1980 ggaacctaca agttccagaa gacagagcta cggaaggagg gctttgaccc ggctattgtg 2040 aaagacccgc tgttctatct agatgcccag aagggccgct acgtcccgct ggaccaagag 2100 gcctacagcc gcatccaggc aggcgaggag aagctgtgat tccccccatc cctctgaggg 2160 ccggcggatg ctggatccgg agccccaggt tccgccccag agcggtcctg gacaaggcca 2220 gaccaaagca agcagggcct ggcacctcca tcctgaggtg ctgcccctcc atccaaaact 2280 gccaagtgac tcattgcctt cccaaccctt ccagaggctt tctgtgaaag tctcatgtcc 2340 aagttccgtc ttctgggctg ggcaggccct ctggttccca ggctgagact gacgggtttt 2400 ctcaggatga tgtcttgggt gagggtaggg agaggacaag gggtcaccga gcccttccca 2460 gagagcaggg agcttataaa tggaaccaga gcagaagtcc ccagactcag gaagtcaaca 2520 gagtgggcag ggacagtggt agcatccatc tggtggccaa agagaatcgt agccccagag 2580 ctgcccaagt tcactgggct ccacccccac ctccaggagg ggaggagagg acctgacatc 2640 tgtaggtggc ccctgatgcc ccatctacag caggaggtca ggaccacgcc cctggcctct 2700 ccccactccc ccatcctcct ccctgggtgg ctgcctgatt atccctcagg cagggcctct 2760 cagtccttgt gggtctgtgt cacctccatc tcagtcttgg cctggctatg aggggaggag 2820 gaatgggaga gggggctcag gggccaataa actctgcctt gagtcctcct aaaaaaaaaa 2880 aaaaaaaaaa aaaaaaaaaa aaaaaaa 2907 53 643 PRT Homo sapiens 53 Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215 220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 54 1248 DNA Homo sapiens misc_feature (1)...(1248) n = A,T,C or G 54 gtcgttggga tcctcggctg cttagatctc ggagccacct gtgttctggc ccccaagttc 60 tctacttcct gcttctggga tgactgtcgg cagcatggcg tgacagtgat cctgtatgtg 120 ggcgagctcc tgcgatactt gtgtaacatt ccccagcaac cagaggaccg gacacataca 180 gtccgcctgg caatgggcaa tggactacgg gctgatgtgt ggggagacct tccagcagcg 240 tttcggtcct atttcggatc tngggaagtc ttacgggctt ccacagaagg gcaacatggg 300 gctttagttc aaatattgtt gggggcgctg cggggccctg ggggcaaaga tggagcttgc 360 ctcctccgaa tgctgtcccc ctttgagctg gtgcagttcg acatggaggc ggcggagcct 420 gtgagggaca atcagggctt ctgcatccct gtagggctag gggagccggg gctgctgttg 480 accaaggtgg taagccagca acccttcgtg ggctaccgcg gcccccgaga gctgtcggaa 540 cggaagctgg tgcgcaacgt gcggcaatcg ggcgacgttt actacaacac cggggacgta 600 ctggccatgg accgcgaagg cttcctctac ttccgcgacc gactcgggga caccttccga 660 tggaagggcg agaacgtgtc cacgcacgag gtggagggcg tgttgtcgca ggtggacttc 720 ttgcaacagg ttaacgtgta tggcgtgtgc gtgccaggtt gtgagggtaa ggtgggcatg 780 gctgctgtgg cattagcccc cggccagact ttcgacgggg agaagttgta ccagcacgtt 840 cgcgcttggc tccctgccta cgctaccccc catttcatcc gcatccagga cgccatggag 900 gtcaccagca cgttcaaact gatgaagacc cggttggtgc gtgagggctt caatgtgggg 960 atcgtggttg accctctgtt tgtactggac aaccgggccc agtccttccg gcccctgacg 1020 gcagaaatgt accaggctgt gtgtgaggga acctggaggc tctgatcacc tggccaaccc 1080 actggggtag ggatcaaagc cagccacccc caccccaaca cactcggtgt ccctttcatc 1140 ctgggcctgt gtgaatccca gcctggccat accctcaacc tcagtgggct ggaaatgaca 1200 gtgggccctg tagcagtggc agaataaact cagmtgygtt cacagaaa 1248 55 354 PRT Homo sapiens VARIANT (1)...(354) Xaa = Any Amino Acid 55 Val Val Gly Ile Leu Gly Cys Leu Asp Leu Gly Ala Thr Cys Val Leu 1 5 10 15 Ala Pro Lys Phe Ser Thr Ser Cys Phe Trp Asp Asp Cys Arg Gln His 20 25 30 Gly Val Thr Val Ile Leu Tyr Val Gly Glu Leu Leu Arg Tyr Leu Cys 35 40 45 Asn Ile Pro Gln Gln Pro Glu Asp Arg Thr His Thr Val Arg Leu Ala 50 55 60 Met Gly Asn Gly Leu Arg Ala Asp Val Trp Gly Asp Leu Pro Ala Ala 65 70 75 80 Phe Arg Ser Tyr Phe Gly Ser Xaa Glu Val Leu Arg Ala Ser Thr Glu 85 90 95 Gly Gln His Gly Ala Leu Val Gln Ile Leu Leu Gly Ala Leu Arg Gly 100 105 110 Pro Gly Gly Lys Asp Gly Ala Cys Leu Leu Arg Met Leu Ser Pro Phe 115 120 125 Glu Leu Val Gln Phe Asp Met Glu Ala Ala Glu Pro Val Arg Asp Asn 130 135 140 Gln Gly Phe Cys Ile Pro Val Gly Leu Gly Glu Pro Gly Leu Leu Leu 145 150 155 160 Thr Lys Val Val Ser Gln Gln Pro Phe Val Gly Tyr Arg Gly Pro Arg 165 170 175 Glu Leu Ser Glu Arg Lys Leu Val Arg Asn Val Arg Gln Ser Gly Asp 180 185 190 Val Tyr Tyr Asn Thr Gly Asp Val Leu Ala Met Asp Arg Glu Gly Phe 195 200 205 Leu Tyr Phe Arg Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu 210 215 220 Asn Val Ser Thr His Glu Val Glu Gly Val Leu Ser Gln Val Asp Phe 225 230 235 240 Leu Gln Gln Val Asn Val Tyr Gly Val Cys Val Pro Gly Cys Glu Gly 245 250 255 Lys Val Gly Met Ala Ala Val Ala Leu Ala Pro Gly Gln Thr Phe Asp 260 265 270 Gly Glu Lys Leu Tyr Gln His Val Arg Ala Trp Leu Pro Ala Tyr Ala 275 280 285 Thr Pro His Phe Ile Arg Ile Gln Asp Ala Met Glu Val Thr Ser Thr 290 295 300 Phe Lys Leu Met Lys Thr Arg Leu Val Arg Glu Gly Phe Asn Val Gly 305 310 315 320 Ile Val Val Asp Pro Leu Phe Val Leu Asp Asn Arg Ala Gln Ser Phe 325 330 335 Arg Pro Leu Thr Ala Glu Met Tyr Gln Ala Val Cys Glu Gly Thr Trp 340 345 350 Arg Leu 56 2885 DNA Homo sapiens 56 aacggcaagt aagcgcaacg caattaatgt gagtagctca ctcattaggc accccaggct 60 ttacacttta tgcttccggg ctcgtatgtt gtgtggaatt gtgagcggat accaatttca 120 cacaggaacc agctatgaca tgattacgaa tttaatacga ctcactatag ggaatttggc 180 cctcgaggcc aagaattcgg cacgaggggt gctgagcccc tgcgcggttt ctggtgcgta 240 gagactgtaa atcgctgcgc ttctcagtca tcatcatccc agcttttccc ggctcgaatt 300 cagcctccaa ctcaagctcg cgggaaagac tacctgagag gagaaaagct tctgtccctg 360 gaccttcttc tgagggtgga gtcggaggct ccctgctttc cagccgccca gtgacccaag 420 cttaatcttc agcaccactt ggggcgacct tttcggtgca aacctacgat tctgtttctc 480 aggattcctc cccatcccgc ttcgccccgg aaaagctgac aagaacttca ggtgtaagcc 540 ctgagtagtg aggatctgcg gtctccgtgg agagctgtgc ctggaagaga aggacgctgg 600 tgggggctga gatcagagct gtcttctggc ccagttgccc ccatgcttct gtcatggcta 660 acagttctag gggctggaat ggtcgtcctg cacttcttgc agaaactcct gttcccttac 720 ttttgggatg acttctggtt cgtgttgaag gtggtgctca ttataattcg gctgaagaag 780 tatgaaaaga gaggggagct ggtgactgtg ctggataaat tcttgagtca tgccaaaaga 840 caacctcgga aacctttcat catctatgag ggagacatct acacctatca ggatgtagac 900 aaaaggagca gcagagtggc ccatgtcttc ctgaaccatt cctctctgaa aaagggggac 960 acggtggctc tgctgatgag caatgagccg gacttcgttc acgtgtggtt cggcctcgcc 1020 aagctgggct gcgtggtggc ctttctcaac accaacattc gctccaactc cctcctgaat 1080 tgcatccgcg cctgtgggcc cagagcccta gtggtgggcg cagatttgct tggaacggta 1140 gaagaaatcc ttccaagcct ctcagaaaat atcagtgttt gggggatgaa agattctgtt 1200 ccacaaggtg taatttcact caaagaaaaa ctgagcacct cacctgatga gcccgtgcca 1260 cgcagccacc atgttgtctc actcctcaag tctacttgtc tttacatttt tacctctgga 1320 acaacaggtc taccaaaagc agctgtgatt agtcagctgc aggttttaag gggttctgct 1380 gtcctgtggg cttttggttg tactgctcat gacattgttt atataaccct tcctctgtat 1440 catagttcag cagctatcct gggaatttct ggatgtgttg agttgggtgc cacttgtgtg 1500 ttaaagaaga aattttcagc aagccagttt tggagtgact gcaagaagta tgatgtgact 1560 gtgtttcagt atattggaga actttgtcgc tacctttgca aacaatctaa gagagaagga 1620 gaaaaggatc ataaggtgcg tttggcaatt ggaaatggca tacggagtga tgtatggaga 1680 gaatttttag acagatttgg aaatataaag gtgtgtgaac tttatgcagc taccgaatca 1740 agcatatctt tcatgaacta cactgggaga attggagcaa ttgggagaac aaatttgttt 1800 tacaaacttc tttccacttt tgacttaata aagtatgact ttcagaaaga tgaacccatg 1860 agaaatgagc agggttggtg tattcatgtg aaaaaaggag aacctggact tctcatttct 1920 cgagtgaatg caaaaaatcc cttctttggc tatgctgggc cttataagca cacaaaagac 1980 aaattgcttt gtgatgtttt taagaaggga gatgtttacc ttaatactgg agacttaata 2040 gtccaggatc aggacaattt cctttatttt tgggaccgta ctggagacac tttcagatgg 2100 aaaggagaaa atgtcgcaac cactgaggtt gctgatgtta ttggaatgtt ggatttcata 2160 caggaagcaa acgtctatgg tgtggctata tcaggttatg aaggaagagc aggaatggct 2220 tctattattt taaaaccaaa tacatcttta gatttggaaa aagtttatga acaagttgta 2280 acatttctac cagcttatgc ttgtccacga tttttaagaa ttcaggaaaa aatggaagca 2340 acaggaacat tcaaactatt gaagcatcag ttggtggaag atggatttaa tccactgaaa 2400 atttctgaac cactttactt catggataac ttgaaaaagt cttatgttct actgaccagg 2460 gaactttatg atcaaataat gttaggggaa ataaaacttt aagattttta tatctagaac 2520 tttcatatgc tttcttagga agagtgagag gggggtatat gattctttat gaaatgggga 2580 aagggagcta acattaatta tgcatgtact atatttcctt aatatgagag ataatttttt 2640 aattgcataa gaattttaat ttcttttaat tgatataaac attagttgat tattcttttt 2700 atctatttgg agattcagtg cataactaag tattttcctt aatactaaag attttaaata 2760 ataaatagtg gctagcggtt tggacaatca ctaaaaatgt actttctaat aagtaaaatt 2820 tctaattttg aataaaagat taaattttac tgaaaaaaaa aaaaaaaaaa aaaattggcg 2880 gccgc 2885 57 619 PRT Homo sapiens 57 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val Val Leu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu Ser His Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val Ala His Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val Ala Leu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe Gly Leu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn Ile Arg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro Arg Ala Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu Glu Ile Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met Lys Asp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu Ser Thr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val Ser Leu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val Leu Arg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 Asp Ile Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270 Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280 285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290 295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys 305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg Leu Ala Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe Leu Asp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala Thr Glu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala Ile Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly Leu Leu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510 Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520 525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530 535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile 545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu Lys His Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu Thr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 610 615 58 3098 DNA Rattus norvegicus 58 aagttcccac tccagacttc tgcgagaacc cgtgaggaag cagcgagaac cgggggtttg 60 caagccagag aaggatgcgg actccgggag caggaacagc ctctgtggcc tcattggggc 120 tgctttggct tctgggactt ccgtggacct ggagcgcggc ggcggcgttc ggtgtgtacg 180 tgggtagcgg tggctggcga tttctgcgta tcgtctgcaa gacggcgagg cgagacctct 240 ttggcctctc tgttctgatc cgcgtgcggc tagagctacg acgacaccgg cgagcaggag 300 acacgatccc acgcatcttc caggccgtgg cccagcgaca gccggagcgc ctggcgctgg 360 tagatgcgag tagcggtatc tgctggacct tcgcacagct agacacctac tccaatgctg 420 tggccaatct gttcctccag ctgggctttg cgccaggcga tgtggtggct gtgttcctgg 480 aaggccggcc cgagttcgtg ggactgtggc tgggcctggc caaggccggt gtagtggctg 540 cgcttctcaa tgtcaacctg aggcgggagc cccttgcctt ctgcttgggc acatcagctg 600 ccaaggccct catttatggc ggggagatgg cagcggcggt ggcggaggtg agtgagcagc 660 tggggaagag cctgctcaag ttctgctctg gagatctggg gcctgagagc gtcctgcctg 720 acacgcagct tctggacccc atgcttgctg aggcgcccac cacacccctg gcacaggccc 780 caggcaaggg catggatgat cggctatttt acatctatac ttctgggacc accggacttc 840 ctaaggcggc cattgtggtg cacagcaggt actaccgcat cgcagccttc ggccaccatt 900 cctacagcat gcgggccaac gatgtgctct atgactgcct acctctctac cactcagcag 960 ggaacatcat gggcgtggga cagtgtatca tctacgggtt aacggtggta ctgcgcaaga 1020 agttctccgc cagccgcttc tgggacgact gtgtcaaata taattgcacg gtagtgcagt 1080 acatcggtga aatatgccgc tacctgctaa ggcagccggt tcgcgatgta gagcggcggc 1140 accgcgtgcg cctggccgtg ggtaacggac tgcggccagc catctgggag gagttcacgc 1200 agggtttcgg tgtgcgacag attggcgagt tctacggcgc caccgaatgc aactgcagca 1260 ttgccaacat ggacggcaag gtcggctcct gcggcttcaa cagccgtatc ctcacgcatg 1320 tgtaccccat ccgtctggtc aaggtcaacg aggacacgat ggagccactg agggactccc 1380 aaggcctctg catcccgtgc cagcccgggg aacctgggct tctcgtgggc cagatcaacc 1440 agcaagaccc tctgcggcgc ttcgatggct atgttagtga cagcgccacc aacaagaaga 1500 ttgcccacag cgtgttccga aagggggaca gcgcctacct ttcaggtgac gtgctagtga 1560 tggacgagct ggggtacatg tacttccgtg accgcagcgg ggataccttc cgatggcgcg 1620 gcgagaacgt atccaccacg gaggtggaag ccgtgctgag ccgcctgttg ggccagacgg 1680 acgtggctgt gtatggagtg gctgtgccag gagtggaggg gaaaagcggc atggcggcca 1740 ttgcagaccc ccacaaccag ctggacccta actcaatgta ccaggaattg cagaaggttc 1800 ttgcatccta tgcccagccc atcttcctgc gtcttctgcc ccaagtggat acaacaggca 1860 ccttcaagat ccagaagacc cgactacagc gtgaaggctt tgacccccgc cagacctcag 1920 accggctctt ctttctagac ctgaaacagg gacgctacct acccctggat gagagagtcc 1980 atgcccgcat ctgcgcaggc gacttctcac tctgagcctg gtgagtggga tggccctgga 2040 cttgtgagac cagggagccg gacacccctg ttcaggtgtt tctcctgcct ggccacgtgg 2100 ccagcagcac ctgtgggtgc aggaaactgg aacctgagtg gccgggtgtc cctttcctac 2160 aacccaccat gcacacatct agcctctgcc ttggtctttt tctccatctc tttcctccgt 2220 gcccagcagg agccccacag acacattggc tgctgtgtcc tgcagtggga ccggtgtcta 2280 ggggtccatg ctgcaggctg tgacccgcac tggtgcccac ctcccttccc cattgtgcct 2340 taggttcctc cactgtgcgc cggtgaagca agtggggacc cacatagctg ttgtccctgc 2400 tgagggttgg tagcaaatgc accctcatgt cagctgggag acacatgcag tctcccactg 2460 acccccaatc aactgaagat actgttttgt attattgttt tgagataggg tctcactgtg 2520 gaggccaagc tggcctcagg ctcaccactc tactgcctcc gggcaccagc ctgcagtttg 2580 atgacatgta tgcactattg ttctaagggt cttctgagtc cctgctttcc cctcatgtcc 2640 taaaaccttc cagaactgac tctgatcact tggatgtagc tagtgttggc cctgcccacg 2700 tgtgtcaatt caggggtccc caggcatcat ctctggaggc cctaaccttg gcaaagcttg 2760 gatgtcctca catcacagca ggagacccag gaaggttgct gtggtgtctc ttgggcaccc 2820 ctggcggcag ccgtggacat gcttccctgc tgtgatagcc caaactgttg cctatgacat 2880 ttgaggtcta cccttctggc tgccatggtc cccattgaga tctttggtga ctcacctcag 2940 ccaccaagcc aggcctctgc cttccttcag ctctaagggc atgaagggtg tggacagagc 3000 agccacaggc tgcccacagt cacccacatg caagtgttat ttccttgttt gttttaaaaa 3060 aataaacatg ctgagccttg aaaaaaaaaa aaaaaaaa 3098 59 646 PRT Rattus norvegicus 59 Met Arg Thr Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu Gly Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Ala Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Leu Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser Val Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Asn Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290 295 300 Ile Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Gly Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Gln Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ser Gly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 Asn Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Gln Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly Arg Tyr Leu Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 60 2963 DNA Rattus norvegicus 60 gacacagtac tgccgatgtt ggacagagga tcgcttaaca gaacgaaatc tcaaaacaaa 60 ttaacaggac ccggttgctt gatttcccaa atcagaaaag gctcgaaatg tctagagggg 120 ctgactgatg cagcggtgac ccggactgga gacagttgga cgcgatcatc tctggtgctt 180 ttgttcaacc ttgaaacctt cgccacagga gacttgcctg agcagagaag caaacgtgga 240 gaaacaaaga gagatctagc gaaaagcctc tgggaccaag gaggggaggt gggactctgg 300 gttggcggtg gcacctgctg ccggctatta ataatagggt cgcgatgcgt ttataaggtg 360 tttgattaaa caaagactct atgagagaag aataactagc aacagcccca cgtctgagtc 420 gtcgcctccg acctttttca acgtgggttc tttgggccga gcgtcgtttg ccgagaacta 480 gatctcacct gaccccagac gctgaaaaca agcgctgtgg catcctgggc cacccaagct 540 gacaagggcg cgccccctga gcacacgagg tgccccacga gggggaggga cccacagccg 600 tcccgcccgc accgcggtgt ccgctgcggg cacctgcagc cgagccgcca cccgcagtcg 660 cagcgcgtcc ggcggccgaa cccggtcgtc agctcgtcag cacctgctct gcttctctcc 720 cgcccgccgc cgcgctgcac gcctcgagcg ctccctcggc cccggcgggg accggggacc 780 ccgcagccac cgccatgctg cctgtgctct acaccggcct ggcggggctg ctgctgctgc 840 ctctgctgct cacctgctgc tgcccctacc tcctccagga cgtgcggttc ttcctgcaac 900 tggccaacat ggcccggcag gtgcgcagct accggcagcg gcgacccgtg cgcaccatcc 960 tgcatgtctt cttggagcaa gcgcgcaaga ccccgcacaa gcccttcctg ctgtttcgcg 1020 acgagacgct tacctacgcc caggtagacc ggcgcagcaa ccaagtagcg cgagcgctgc 1080 atgatcacct gggcctgcgg cagggggatt gcgtggccct cttcatgggc aatgagccgg 1140 cctacgtgtg gctctggctg ggactgctca aactgggctg tcccatggcg tgcctcaact 1200 acaacatccg tgccaagtct ctgctacact gctttcagtg ctgcggggcg aaggtgctgc 1260 tggcctcccc agagctacac gaagctgtcg aggaggttct tccaaccctg aaaaaggagg 1320 gcgtgtccgt cttctacgta agcagaactt ctaacactaa tggcgtggac acagtactgg 1380 acaaagtaga cggggtgtcg gcggacccca tcccggagtc gtggaggtct gaagtcacgt 1440 tcaccacacc cgcagtctac atatatactt cgggcaccac aggtcttcca aaggctgcaa 1500 ccattaatca ccatcgcctc tggtatggga ccagccttgc cctgaggtcc ggaattaagg 1560 ctcatgacgt catctacacc accatgcccc tgtaccacag cgcggcgctc atgattggcc 1620 tccacggatg cattgtggtt ggggctacat ttgctttgcg gagcaaattt tcagccagcc 1680 agttttggga cgactgcagg aaatacaacg ccactgtcat tcagtacatc ggtgaactgc 1740 ttcggtacct ctgcaacacg ccccagaaac caaatgaccg ggaccacaaa gtgaaaatag 1800 cactaggaaa tggcttacga ggagatgtgt ggagagagtt catcaagaga tttggggaca 1860 ttcacattta tgagttctac gcttccactg aaggcaacat tggatttatg aactatccaa 1920 gaaaaatcgg agctgttgga agagaaaatt acctacaaaa aaaagttgta aggcacgagc 1980 tgatcaagta tgacgtggag aaggatgagc ctgtccgtga tgcaaatgga tattgcatca 2040 aagtccccaa aggagaggtt ggactcttga tttgcaaaat cacagagctc acaccatttt 2100 ttggctatgc tggaggaaag acccagacag agaagaaaaa gctcagagat gtttttaaga 2160 aaggagacgt ctacttcaac agtggcgatc tcctgatgat cgaccgtgaa aatttcatct 2220 attttcacga cagagttgga gacaccttcc ggtggaaagg agagaatgta gctaccacgg 2280 aagtcgctga cattgtggga ctggtagatt ttgttgaaga agtgaatgtt tacggtgtgc 2340 ccgtgccagg tcatgaaggt cgcatcggga tggcctcgat caagatgaaa gaaaactacg 2400 agttcaatgg aaagaaactc tttcagcaca tctcggagta cctgcccagt tactcgaggc 2460 ctcggttcct gagaatacaa gataccattg agatcaccgg gacttttaaa caccgcaaag 2520 tgaccctgat ggaagagggc tttaacccct cagtcatcaa agataccttg tatttcatgg 2580 atgacacaga aaaaacatac gtgcccatga ctgaggacat ttataatgcc ataattgata 2640 agactctgaa gctctgaatg ttgcctggct cctaacactt ccagaaagaa acacaatagg 2700 cctagcatag ccccttcaca tgtgtaatcc aactttaact tgattaaagg ttataggtgt 2760 gatttttcct aggaaattat tcatttaaag gacaattgtt tgtttgtttg tttgtttttt 2820 attaattaca ccagaacgtt tgcaagtaaa aagatttaaa gtcacttatt tttcaatgtg 2880 cacctgccat ttgtccttgc aaacttagct tcttggagag agggccttat ttttttaaag 2940 acataataaa ctatgtaaac act 2963 61 620 PRT Rattus norvegicus 61 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly Leu Leu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu Leu Gln Asp Val Arg Phe 20 25 30 Phe Leu Gln Leu Ala Asn Met Ala Arg Gln Val Arg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu His Val Phe Leu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp His Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Leu Trp Leu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Ala Ser Pro Glu 145 150 155 160 Leu His Glu Ala Val Glu Glu Val Leu Pro Thr Leu Lys Lys Glu Gly 165 170 175 Val Ser Val Phe Tyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Val Leu Asp Lys Val Asp Gly Val Ser Ala Asp Pro Ile Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Thr Ile Asn His His 225 230 235 240 Arg Leu Trp Tyr Gly Thr Ser Leu Ala Leu Arg Ser Gly Ile Lys Ala 245 250 255 His Asp Val Ile Tyr Thr Thr Met Pro Leu Tyr His Ser Ala Ala Leu 260 265 270 Met Ile Gly Leu His Gly Cys Ile Val Val Gly Ala Thr Phe Ala Leu 275 280 285 Arg Ser Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Ala Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val Lys Ile Ala 325 330 335 Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Glu Phe Ile Lys Arg 340 345 350 Phe Gly Asp Ile His Ile Tyr Glu Phe Tyr Ala Ser Thr Glu Gly Asn 355 360 365 Ile Gly Phe Met Asn Tyr Pro Arg Lys Ile Gly Ala Val Gly Arg Glu 370 375 380 Asn Tyr Leu Gln Lys Lys Val Val Arg His Glu Leu Ile Lys Tyr Asp 385 390 395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys 405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Ile Cys Lys Ile Thr Glu Leu 420 425 430 Thr Pro Phe Phe Gly Tyr Ala Gly Gly Lys Thr Gln Thr Glu Lys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Val Tyr Phe Asn Ser Gly 450 455 460 Asp Leu Leu Met Ile Asp Arg Glu Asn Phe Ile Tyr Phe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu Val Asn Val 500 505 510 Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly Met Ala Ser 515 520 525 Ile Lys Met Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ser Glu Tyr Leu Pro Ser Tyr Ser Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr Phe Lys His Arg Lys Val 565 570 575 Thr Leu Met Glu Glu Gly Phe Asn Pro Ser Val Ile Lys Asp Thr Leu 580 585 590 Tyr Phe Met Asp Asp Thr Glu Lys Thr Tyr Val Pro Met Thr Glu Asp 595 600 605 Ile Tyr Asn Ala Ile Ile Asp Lys Thr Leu Lys Leu 610 615 620 62 1350 DNA Rattus norvegicus 62 gatcagctct tctatatcta cacgtcgggc accacggggc tacccaaagc tgccattgtg 60 gtgcacagca ggtattaccg aatggctgcc ctggtgtact atggattccg catgcggcct 120 gatgacattg tctatgactg cctccccctc taccactcag caggaaacat tgtggggatt 180 ggccagtgcg tactccacgg catgactgtg gtgatccgga agaagttttc agcctcccgg 240 ttctgggatg actgtatcaa gtacaactgc acaattgtac agtacattgg tgagctttgc 300 cgctacctcc tgaaccagcc accccgtgag gctgagtctc ggcacaaggt gcgcatggca 360 ctgggcaacg gtctccggca gtccatctgg accgacttct ccagccgttt ccacattccc 420 aaggtggccg agttctacgg ggccaccgag tgcaactgta gcttgggcaa ctttgacagc 480 caggtggggg cctgtggctt caatagccgc atcctgtcct ttgtgtaccc catccgcttg 540 gtacgagtca atgaggatac catggaactg atccggggac ccgatggcgt ctgcattccc 600 tgtcaaccag gccagccagg ccagctggtg ggtcgcatca tccagcagga ccccctacgc 660 cgttttgatg gctacctcaa ccagggtgcc aacaacaaga agattgctag tgatgtcttc 720 aagaaagggg accaagccta cctcactggt gacgtgctgg tgatggatga gctgggctac 780 ctgtacttcc gagaccgcac aggggacacg ttccgctgga aaggggagaa tgtgtctacc 840 actgaagtgg agggcacact cagccgcctg cttcagatgg cagatgtggc tgtttatggt 900 gttgaggtgc caggagctga gggccgagca ggaatggctg ctgtggcaag ccccactagc 960 aactgtgacc tggagagctt tgcacagacc ttgaaaaagg agctgcccct gtacgcccgc 1020 cccatcttcc tccgcttctt gcctgagctg cacaaaacag gaaccttcaa gttccagaag 1080 acagagttgc ggaaggaggg ctttgacccg tctgttgtga aagacccact cttctatttg 1140 gatgcccgga caggctgcta tgttgcactg gaccaagagg cctatacccg catccaggca 1200 ggcgaggaga agctgtgatt tcccccacat ccctctgagg gccagaggat gctggattca 1260 gagccccagc ttccactcca gaaggggtct gggcaaggcc agaccaaagc tagcagggcc 1320 cgcaccttca ccctaggtgc tgatccccct 1350 63 405 PRT Rattus norvegicus 63 Asp Gln Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys 1 5 10 15 Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val 20 25 30 Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu 35 40 45 Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Val 50 55 60 Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg 65 70 75 80 Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile 85 90 95 Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu 100 105 110 Ser Arg His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser 115 120 125 Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile Pro Lys Val Ala Glu 130 135 140 Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser 145 150 155 160 Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr 165 170 175 Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg 180 185 190 Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln 195 200 205 Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly 210 215 220 Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Ser Asp Val Phe 225 230 235 240 Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp 245 250 255 Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg 260 265 270 Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser 275 280 285 Arg Leu Leu Gln Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro 290 295 300 Gly Ala Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Ser 305 310 315 320 Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro 325 330 335 Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys 340 345 350 Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe 355 360 365 Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Thr 370 375 380 Gly Cys Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala 385 390 395 400 Gly Glu Glu Lys Leu 405 64 3217 DNA Mus musculus 64 atgcgggctc ctggagcagg aacagcctct gtggcctcac tggcgctgct ttggtttctg 60 ggacttccgt ggacctggag cgcggcggcg gcgttctgtg tgtacgtggg tggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacg gcgaggcgag acctctttgg cctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacga caccggcgag caggagacac gatcccgtgc 240 atcttccagg ctgtggcccg gcgacaacca gagcgcctgg cactggtgga cgccagtagt 300 ggtatatgct ggaccttcgc acagctggac acctactcca atgctgtagc caacctgttc 360 cgccagctgg gctttgcacc aggcgatgtg gtggctgtgt tcctggaggg ccggccggag 420 ttcgtgggac tgtggctggg cctggccaag gccggtgtgg tggctgctct tctcaatgtc 480 aacctgaggc gggagcccct ggccttctgc ctgggcacat cagctgccaa ggccctcatt 540 tatggcgggg agatggcagc ggcggtggcg gaggtgagcg agcagctggg gaagagcctc 600 ctcaagttct gctctggaga tctggggcct gagagcatcc tgcctgacac gcagctcctg 660 gaccccatgc ttgctgaggc gcccaccaca cccctggcac aagccccagg caagggcatg 720 gatgatcggc tgttttacat ctatacttct gggaccaccg ggcttcctaa ggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgct gcctttggcc accattccta cagcatgcgt 840 gccgccgatg tgctctatga ctgcctgcca ctctaccact ctgcagggaa catcatgggt 900 gtggggcagt gcgtcatcta cgggttgacg gtggtactgc gcaagaagtt ctccgccagc 960 cgcttctggg atgactgtgt caagtacaat tgcacggtag tggatgacat aggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgc gacgtggagc agcgacaccg cgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatc tgggaggagt tcacgcagcg cttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctacc gagtgcaact gcagcattgc caacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagc cgtatcctca cgcatgtgta ccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggag ccactgcggg actccgaggg cctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctc gtgggccaga tcaaccagca ggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagt gccaccaaca agaagattgc ccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctca ggtgacgtgc tagtgatgga cgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggac accttccgct ggcgcgggga gaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgc ctactgggcc agacggacgt ggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaa gctggcatgg cagccatcgc agatccccac 1680 agccagttgg accctaactc aatgtaccag gaattacaga aggttcttgc atcctatgct 1740 cggcccatct tcctgcgtct tctgccccag gtggatacca caggcacctt caagatccag 1800 aagacccggc tgcagcgtga aggctttgac ccccgtcaga cctcagacag gctcttcttt 1860 ctagacctga agtccggcac gaggtatcta cccctggatg agagagtcca tgcccgcatt 1920 tgcgcaggcg acttctcact ctgagcctgg agagtgggct gggcctggac tcctgagacc 1980 tgggagcctg acacccctct tcgggtgctt ctcctgcctg gccacatgga cagcagcacc 2040 tgtgagagta ggaaaatgga acctgagtgg ctgggacccc tctcctactt cccactatgc 2100 atccattttg cctctgcctt gatctttttc tccatctctt ttctccctac ccagcaggag 2160 ccccacaaac acatgttggc tgctgtgtcc tgcagttgga ccagtgtcca ggggtacagg 2220 cttcaggctg tgacccacac tggtacccac ctccctttcc tattttgcct taggttcatc 2280 cacggttccc ctgtggagca agtgggggcc cacatagctg ctgtccctgc tgagggttgg 2340 tagcaatcac accctcatgt cagctgggag acacgcgcag tctcccactg acccccaatc 2400 aactgaaaat attgttttga ctactttttg tttttttgtt tttttgtttt tttttttttt 2460 cgagacagag tttctctgta tagccctggc tgtcctggaa ctcactttgt agaccaggct 2520 ggcctcgaac tcaaaaatcc tcctgactct gcctctgctt cccaagtgct gggattaaag 2580 acgtgcgcca ccaccgcctg gctgttttgt atttttgttt tgttttgacg atagggtctc 2640 actgtggagg ccaagctggc ctcagactcc ccaccccatt gcctctgggc accattctat 2700 attctcagac tgatgacaat gcactagtgt ccctaggagt cttgagtctg cactttcccc 2760 tcatagcctc aagcttccag aactgactct gatcacttgg atgtggctag tgttggctct 2820 acccacatgt gtcaattcag gggtccccag gcatagtctc tggaagccct cacccggaaa 2880 aagcttggag agacccagga aggttgttgt gttctcttgg gcaccccctg gtggcagtcc 2940 tgggcatgct tccgcactgt actggtgcat atagcccaga cctatgacat ttgaggtcta 3000 cccttctggc tcctgtggtc cccattgaga tccttggtga ctcacctcag tcaccaagca 3060 gagcctctgc ctgccttcat cttcaaggtc atgaaggatg tggacagagc agctacaggc 3120 tgccagcagt caaccacatg agagtgttac ttccttgttg gtttttaaaa aataaatgtg 3180 ctgagcctcg aaaaaaaaaa aaaaaaaaaa aaaaaaa 3217 65 646 PRT Mus musculus 65 Met Arg Ala Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly Gly Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala Val Ala Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly Arg Tyr Val Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 66 2338 DNA Mus musculus 66 gggcggaggc cgagcccagt cgccagctcc tgctctgctc ctctcccgcc tgccgccgcg 60 ctgcacgcct cgagcactcc ctcggccccg gcggggaccg gggaccccgc agctaccgcc 120 atgctgccag tgctctacac cggcctggcg gggctgctgc tgctgcctct gctgctcacc 180 tgctgctgcc cctacctcct ccaagatgtg cggtacttcc tgcggctggc caacatggcc 240 cggcgggtgc gcagctaccg gcagcggcga cccgtgcgta ccatcctgcg ggccttcctg 300 gaacaagcgc gcaagacccc acacaagccc ttcctgctgt tccgagacga gacgctcacc 360 tacgcccagg tggaccggcg cagcaaccaa gtggcgcggg cgctgcacga tcaactgggc 420 ctacgacagg gggattgcgt agccctcttc atgggcaatg agccggccta cgtgtggatc 480 tggctgggac tgctcaaact gggctgtccc atggcgtgcc tcaactacaa cattcgtgcc 540 aagtctctgc tgcactgctt tcaatgctgc ggggcgaagg tgctgctggc ctccccagat 600 ctacaagaag ctgtggagga ggttcttcca accctgaaaa aggatgccgt gtccgtcttt 660 tacgtaagca gaacttctaa cacaaatggt gtggacacaa tactggacaa agtagacgga 720 gtgtcggcgg aacccacccc ggagtcgtgg aggtctgaag tcacttttac cacgccagca 780 gtatacattt atacttcggg aaccacaggt cttccaaaaa gcggaaccat caatcatcat 840 cgcctaaggt atgggacaag ccttgctatg tcgagtggga atcacggcca aggatgtcat 900 ctataccaac aatgcccctg ttccaacagt gcaacgctca agatcggcct tcacggatgc 960 atcctgggtt ggggctactt taaccttggc ggggcaaatt ctcaagcaag ccaattttgg 1020 gaacgactgg caggaaatac aacgtcaacg gtcattcagt acattggtga actgcttcgg 1080 tacctgtgca acacaccgca gaaaccaaat gaccgggacc acaaagtgaa aaaagccctg 1140 ggaaatggct tacgaggaga tgtgtggaga gagttcatca agagatttgg ggacatccac 1200 gtgtatgagt tctacgcatc cactgaaggc aacattggat ttgtgaacta tccaaggaaa 1260 atcggtgctg tcgggagagc aaactaccta caaagaaaag ttgcaaggta tgagctgatc 1320 aagtatgacg tggagaagga cgagccggtc cgtgacgcaa atggatattg catcaaagtc 1380 cccaaaggtg aggttggact cttggtttgc aaaatcacac agctcacacc atttattggc 1440 tatgctggag gaaagaccca gacagagaag aaaaaactca gagatgtctt taagaaaggc 1500 gacatctact tcaacagcgg agacctcctg atgatcgacc gtgagaactt cgtctacttt 1560 cacgacaggg ttggagatac tttccggtgg aaaggagaga acgtagctac cacagaagtc 1620 gctgacatcg tgggactggt agattttgtt gaagaagtga atgtgtatgg cgtgcctgtg 1680 ccaggtcatg agggtcgaat tgggatggcc tccctcaaga tcaaagaaaa ctacgagttc 1740 aatggaaaga aactctttca acacatcgcg gagtacctgc ccagttacgc gaggcctcgg 1800 ttcctgagga tacaagatac cattgagatc actgggactt ttaaacaccg caaagtgacc 1860 ctgatggaag agggcttcaa tcccacagtc atcaaagata ccttgtattt catggatgat 1920 gcagagaaaa catttgtgcc catgactgag aacatttata atgccataat tgataaaact 1980 ctgaagctct gaatattccc tggtggttta gctcatgaca tttccagaaa gaaactcgat 2040 agacctcgca gagccacttc atacgtagaa tccaacttta acttgattga agactataag 2100 gtgcgatttt atttttagga aattattcat taaaaggata gttttttttt ttttttttaa 2160 ttacacctga acctttgcaa gtaaaaagat ttagagacaa ttatttttca atgtgcacct 2220 gccatttgtc cttgcaaact aagcttcttg gagagagggc cttatttttt taaagacata 2280 ataaactata ttaacactaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2338 67 623 PRT Mus musculus 67 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly Leu Leu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu Leu Gln Asp Val Arg Tyr 20 25 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg Val Arg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala Phe Leu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile Trp Leu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Ala Ser Pro Asp 145 150 155 160 Leu Gln Glu Ala Val Glu Glu Val Leu Pro Thr Leu Lys Lys Asp Ala 165 170 175 Val Ser Val Phe Tyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Ile Leu Asp Lys Val Asp Gly Val Ser Ala Glu Pro Thr Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Gly Thr Ile Asn His His 225 230 235 240 Arg Leu Arg Tyr Gly Thr Ser Leu Ala Met Ser Ser Gly Asn His Gly 245 250 255 Gln Gly Cys His Leu Tyr Gln Gln Cys Pro Cys Ser Asn Ser Ala Thr 260 265 270 Leu Lys Ile Gly Leu His Gly Cys Ile Leu Gly Trp Gly Tyr Phe Asn 275 280 285 Leu Gly Gly Ala Asn Ser Gln Ala Ser Gln Phe Trp Glu Arg Leu Ala 290 295 300 Gly Asn Thr Thr Ser Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg 305 310 315 320 Tyr Leu Cys Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val 325 330 335 Lys Lys Ala Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Glu Phe 340 345 350 Ile Lys Arg Phe Gly Asp Ile His Val Tyr Glu Phe Tyr Ala Ser Thr 355 360 365 Glu Gly Asn Ile Gly Phe Val Asn Tyr Pro Arg Lys Ile Gly Ala Val 370 375 380 Gly Arg Ala Asn Tyr Leu Gln Arg Lys Val Ala Arg Tyr Glu Leu Ile 385 390 395 400 Lys Tyr Asp Val Glu Lys Asp Glu Pro Val Arg Asp Ala Asn Gly Tyr 405 410 415 Cys Ile Lys Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys Ile 420 425 430 Thr Gln Leu Thr Pro Phe Ile Gly Tyr Ala Gly Gly Lys Thr Gln Thr 435 440 445 Glu Lys Lys Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Ile Tyr Phe 450 455 460 Asn Ser Gly Asp Leu Leu Met Ile Asp Arg Glu Asn Phe Val Tyr Phe 465 470 475 480 His Asp Arg Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 485 490 495 Thr Thr Glu Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu 500 505 510 Val Asn Val Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly 515 520 525 Met Ala Ser Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys 530 535 540 Leu Phe Gln His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro Arg 545 550 555 560 Phe Leu Arg Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr Phe Lys His 565 570 575 Arg Lys Val Thr Leu Met Glu Glu Gly Phe Asn Pro Thr Val Ile Lys 580 585 590 Asp Thr Leu Tyr Phe Met Asp Asp Ala Glu Lys Thr Phe Val Pro Met 595 600 605 Thr Glu Asn Ile Tyr Asn Ala Ile Ile Asp Lys Thr Leu Lys Leu 610 615 620 68 1998 DNA Mus musculus 68 gaaagctctg agagcgggtg cagtctggcc tggcgtctcg cgtacctggc ccgggagcag 60 ccgacacaca ccttcctcat ccacggcgcg cagcgcttta gctacgcgga ggctgagcgc 120 gagagcaacc ggattgctcg cgcctttctg cgcgcacggg gctggaccgg gggccgccga 180 ggctcgggca ggggcagcac tgaggaaggc gcacgcgtgg cgcctccggc tggagatgcg 240 gctgctagag ggacgaccgc gccccctctg gcacccgggg cgaccgtggc gctgctcctc 300 ccagcgggcc cggatttcct ttggatttgg ttcggactgg ccaaagctgg cctgcgcacg 360 gcctttgtgc ccaccgcttt acgccgagga cccctgctgc actgcctccg cagctgcggt 420 gcgagtgcgc tcgtgctggc cacagagttc ctggagtccc tggagccgga cctgccggcc 480 ttgagagcca tggggctcca cctatgggcg acgggccctg aaactaatgt agctggaatc 540 agcaatttgc tatcggaagc agcagaccaa gtggatgagc cagtgccggg gtacctctct 600 gccccccaga acataatgga cacctgcctg tacatcttca cctctggcac tactggcctg 660 cccaaggctg ctcgaatcag tcatctgaag gttctacagt gccagggatt ctaccatctg 720 tgtggagtcc accaggagga cgtgatctac ctcgcactcc cactgtacca catgtctggc 780 tcccttctgg gcattgtggg ctgcttgggc attggggcca ccgtggtgct gaaacccaag 840 ttctcagcta gccagttctg ggacgattgc cagaaacaca gggtgacagt gttccagtac 900 attggggagt tgtgccgata cctcgtcaac cagcccccga gcaaggcaga gtttgaccat 960 aaggtgcgct tggcagtggg cagtgggttg cgcccagaca cctgggagcg tttcctgcgg 1020 cgatttggac ctctgcagat actggagacg tatggcatga cagagggcaa cgtagctacg 1080 ttcaattaca caggacggca gggtgcagtg gggcgagctt cctggcttta caagcacatc 1140 ttccccttct ccttgattcg atacgatgtc atgacagggg agcctattcg gaatgcccag 1200 gggcactgca tgaccacatc tccaggtgag ccaggcctac tggtggcccc agtgagccag 1260 cagtccccct tcctgggcta tgctggggct ccggagctgg ccaaggacaa gctgctgaag 1320 gatgtcttct ggtctgggga cgttttcttc aatactgggg acctcttggt ctgtgatgag 1380 caaggctttc ttcacttcca cgatcgtact ggagacacca tcaggtggaa gggagagaat 1440 gtggccacaa ctgaagtggc tgaggtcttg gagaccctgg acttccttca ggaggtgaac 1500 atctatggag tcacggtgcc agggcacgaa ggcagggcag gcatggcggc cttggctctg 1560 cggcccccgc aggctctgaa cctggtgcag ctctacagcc atgtttctga gaacttgcca 1620 ccgtatgccc gacctcggtt tctcaggctc caggaatctt tggccactac tgagaccttc 1680 aaacagcaga aggttaggat ggccaatgag ggctttgacc ccagtgtact gtctgaccca 1740 ctctatgttc tggaccaaga tataggggcc tacctgcccc tcacacctgc ccggtacagt 1800 gccctcctgt ctggagacct tcgaatctga aaccttccac ttgagggagg ggctcggagg 1860 gtacaggcca ccatggctgc accagggagg gttttcgggt atcttttgta tatggagtca 1920 ttattttgta ataaacagct ggagcttaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1980 aaaaaaaaaa aaaaaaaa 1998 69 609 PRT Mus musculus 69 Glu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg Leu Ala Tyr Leu 1 5 10 15 Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His Gly Ala Gln Arg 20 25 30 Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg Ile Ala Arg Ala 35 40 45 Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg Gly Ser Gly Arg 50 55 60 Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro Ala Gly Asp Ala 65 70 75 80 Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro Gly Ala Thr Val 85 90 95 Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp Ile Trp Phe Gly 100 105 110 Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala Leu Arg 115 120 125 Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly Ala Ser Ala Leu 130 135 140 Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu Pro Ala 145 150 155 160 Leu Arg Ala Met Gly Leu His Leu Trp Ala Thr Gly Pro Glu Thr Asn 165 170 175 Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala Asp Gln Val Asp 180 185 190 Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro Gln Asn Ile Met Asp Thr 195 200 205 Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 210 215 220 Arg Ile Ser His Leu Lys Val Leu Gln Cys Gln Gly Phe Tyr His Leu 225 230 235 240 Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala Leu Pro Leu Tyr 245 250 255 His Met Ser Gly Ser Leu Leu Gly Ile Val Gly Cys Leu Gly Ile Gly 260 265 270 Ala Thr Val Val Leu Lys Pro Lys Phe Ser Ala Ser Gln Phe Trp Asp 275 280 285 Asp Cys Gln Lys His Arg Val Thr Val Phe Gln Tyr Ile Gly Glu Leu 290 295 300 Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Phe Asp His 305 310 315 320 Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr Trp Glu 325 330 335 Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu Glu Thr Tyr Gly 340 345 350 Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr Gly Arg Gln Gly 355 360 365 Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro Phe Ser 370 375 380 Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile Arg Asn Ala Gln 385 390 395 400 Gly His Cys Met Thr Thr Ser Pro Gly Glu Pro Gly Leu Leu Val Ala 405 410 415 Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Ala Pro Glu 420 425 430 Leu Ala Lys Asp Lys Leu Leu Lys Asp Val Phe Trp Ser Gly Asp Val 435 440 445 Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Glu Gln Gly Phe Leu 450 455 460 His Phe His Asp Arg Thr Gly Asp Thr Ile Arg Trp Lys Gly Glu Asn 465 470 475 480 Val Ala Thr Thr Glu Val Ala Glu Val Leu Glu Thr Leu Asp Phe Leu 485 490 495 Gln Glu Val Asn Ile Tyr Gly Val Thr Val Pro Gly His Glu Gly Arg 500 505 510 Ala Gly Met Ala Ala Leu Ala Leu Arg Pro Pro Gln Ala Leu Asn Leu 515 520 525 Val Gln Leu Tyr Ser His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg 530 535 540 Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr Phe 545 550 555 560 Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro Ser Val 565 570 575 Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile Gly Ala Tyr Leu 580 585 590 Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser Gly Asp Leu Arg 595 600 605 Ile 70 2710 DNA Mus musculus 70 atgctgcttg gagcctctct ggtgggggcg ctactgttct ccaagctagt gctgaagctg 60 ccctggaccc aggtgggatt ctccctgttg ctcctgtact tggggtctgg tggctggcgt 120 ttcatccggg tcttcatcaa gacggtcagg agagatatct ttggtggcat ggtgctcctg 180 aaggtgaaga ccaaggtgcg acggtacctt caggagcgga agacggtgcc cctgctgttt 240 gcttcaatgg tacagcgcca cccggacaag acagccctga ttttcgaggg cacagacact 300 cactggacct tccgccagct ggatgagtac tccagtagtg tggccaactt cctgcaggcc 360 cggggcctgg cctcaggcaa tgtagttgcc ctctttatgg aaaaccgcaa tgagtttgtg 420 ggtctgtggc taggcatggc caagctgggc gtggaggcgg ctctcatcaa caccaacctt 480 aggcgggatg ccctgcgcca ctgtcttgac acctcaaagg cacgagctct catctttggc 540 agtgagatgg cctcagctat ctgtgagatc catgctagcc tggagcccac actcagcctc 600 ttctgctctg gatcctggga gcccagcaca gtgcccgtca gcacagagca tctggaccct 660 cttctggaag atgccccgaa gcacctgccc agtcacccag acaagggttt tacagataag 720 ctcttctaca tctacacatc gggcaccacg gggctaccca aagctgccat tgtggtgcac 780 agcaggtatt atcgtatggc ttccctggtg tactatggat tccgcatgcg gcctgatgac 840 attgtctatg actgcctccc cctctaccac tcaagcagga aacatcgtgg ggattggcag 900 tgcttactcc acggcatgac tgtggtgatc cggaagaagt tctcagcctc ccggttctgg 960 gatgattgta tcaagtacaa ctgcacagtg gtacagtaca ttggcgagct ctgccgctac 1020 ctcctgaacc agccaccccg tgaggctgag tctcggcaca aggtgcgcat ggcactgggc 1080 aacggtctcc ggcagtccat ctggaccgac ttctccagcc gtttccacat cccccaggtg 1140 gctgagttct atggggccac tgaatgcaac tgtagcctgg gcaactttga cagccgggtg 1200 ggggcctgtg gcttcaatag ccgcatcctg tcctttgtgt accctatccg tttggtacgt 1260 gtcaatgagg ataccatgga actgatccgg ggacccgatg gagtctgcat tccctgtcaa 1320 ccaggtcagc caggccagct ggtgggtcgc atcatccagc aggaccctct gcgccgtttc 1380 gacgggtacc tcaaccaggg tgccaacaac aagaagattg ctaatgatgt cttcaagaag 1440 ggggaccaag cctacctcac tggtgacgtc ctggtgatgg atgagctggg ttacctgtac 1500 ttccgagatc gcactgggga cacgttccgc tggaaagggg agaatgtatc taccactgag 1560 gtggagggca cactcagccg cctgcttcat atggcagatg tggcagttta tggtgttgag 1620 gtgccaggaa ctgaaggccg agcaggaatg gctgccgttg caagtcccat cagcaactgt 1680 gacctggaga gctttgcaca gaccttgaaa aaggagctgc ctctgtatgc ccgccccatc 1740 ttcctgcgct tcttgcctga gctgcacaag acagggacct tcaagttcca gaagacagag 1800 ttgcggaagg agggctttga cccatctgtt gtgaaagacc cgctgttcta tctggatgct 1860 cggaagggct gctacgttgc actggaccag gaggcctata cccgcatcca ggcaggcgag 1920 gagaagctgt gatttccccc tacatccctc tgagggccag aagatgctgg attcagagcc 1980 ctagcgtcca ccccagaggg tcctgggcaa tgccagacca aagctagcag ggcccgcacc 2040 tccgccccta ggtgctgatc tcccctctcc caaactgcca agtgactcac tgccgcttcc 2100 ccgaccctcc agaggctttc tgtgaaagtc tcatccaagc tgtgtcttct ggtccaggcg 2160 tggcccctgg ccccagggtt tctgataggc tcctttagga tggtatcttg ggtccagcgg 2220 gccagggtgt gggagaggag tcactaagat ccctccaatc agaagggagc ttacaaagga 2280 accaaggcaa agcctgtaga ctcaggaagc taagtggcca gagactatag tggccagtca 2340 tcccatgtcc acagaggatc ttggtccaga gctgccaaag tgtcacctct ccctgcctgc 2400 acctctgggg aaaagaggac agcatgtggc cactgggcac ctgtctcaag aagtcaggat 2460 cacacactca gtccttgttt ctccaggttc ccttgttctt gtctcgggga gggagggacg 2520 agtgtcctgt ctgtccttcc tgcctgtctg tgagtctgtg ttgcttctcc atctgtccta 2580 gcctgagtgt gggtggaaca ggcatgagga gagtgtggct caggggccaa taaactctgc 2640 cttgactcct cttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaa 2710 71 643 PRT Mus musculus 71 Met Leu Leu Gly Ala Ser Leu Val Gly Ala Leu Leu Gly Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Leu Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 Ala Ser Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120 125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys Ala Arg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Ile His Ala 180 185 190 Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu Asp Pro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro Ser His Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser Arg Lys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350 His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu His Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610 615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 72 2277 DNA Mus musculus 72 cactcatcag agctaagaga gactacacgc tctcatctac ttcagaaaga gccaatgcca 60 tgggtatttg gaagaaacta accttactgc tgttgctgct tctgctggtt ggcctggggc 120 agcccccatg gccagcagct atggctctgg ccctgcgttg gttcctggga gaccccacat 180 gccttgtgct gcttggcttg gcattgctgg gcagaccctg gatcagctcc tggatgcccc 240 actggctgag cctggtagga gcagctctta ccttattcct attgcctcta cagccacccc 300 cagggctacg ctggctgcat aaagatgtgg ctttcacctt caagatgctt ttctatggcc 360 taaagttcag gcgacgcctt aacaaacatc ctccagagac ctttgtggat gctttagagc 420 ggcaagcact ggcatggcct gaccgggtgg ccttggtgtg tactgggtct gagggctcct 480 caatcacaaa tagccagctg gatgccaggt cctgtcaggc agcatgggtc ctgaaagcaa 540 agctgaagga tgccgtaatc cagaacacaa gagatgctgc tgctatctta gttctcccgt 600 ccaagaccat ttctgctttg agtgtgtttc tggggttggc caagttgggc tgccctgtgg 660 cctggatcaa tccacacagc cgagggatgc ccttgctaca ctctgtacgg agctctgggg 720 ccagtgtgct gattgtggat ccagacctcc aggagaacct ggaagaagtc cttcccaagc 780 tgctagctga gaacattcac tgcttctacc ttggccacag ctcacccacc ccgggagtag 840 aggctctggg agcttccctg gatgctgcac cttctgaccc agtacctgcc agccttcgag 900 ctacgattaa gtggaaatct cctgccatat tcatctttac ttcagggacc actggactcc 960 caaagccagc catcttatca catgagcggg tcatacaagt gagcaacgtg ctgtccttct 1020 gtggatgcag agctgatgat gtggtctatg acgtcctacc tctgtaccat acgatagggc 1080 ttgtccttgg attccttggc tgcttacaag ttggagccac ctgtgtcctg gcccccaagt 1140 tctctgcctc ccgattctgg gctgagtgcc ggcagcatgg cgtaacagtg atcttgtatg 1200 tgggtgaaat cctgcggtac ttgtgtaacg tccctgagca accagaagac aagatacata 1260 cagtgcgctt ggccatggga actggacttc gggcaaatgt gtggaaaaac ttccagcaac 1320 gctttggtcc cattcggatc tgggaattct acggatccac agagggcaat gtgggcttaa 1380 tgaactatgt gggccactgc ggggctgtgg gaaggaccag ctgcatcctt cgaatgctga 1440 ctccctttga gcttgtacag ttcgacatag agacagcaga gcctctgagg gacaaacagg 1500 gtttttgcat tcctgtggag ccaggaaagc caggacttct tttgaccaag gttcgaaaga 1560 accaaccctt cctgggctac cgtggttccc aggccgagtc caatcggaaa cttgttgcga 1620 atgtacgacg cgtaggagac ctgtacttca acactgggga cgtgctgacc ttggaccagg 1680 aaggcttctt ctactttcaa gaccgccttg gtgacacctt ccggtggaag ggcgaaaacg 1740 tatctactgg agaggtggag tgtgttttgt ctagcctaga cttcctagag gaagtcaatg 1800 tctatggtgt gcctgtgcca gggtgtgagg gtaaggttgg catggctgct gtgaaactgg 1860 ctcctgggaa gacttttgat gggcagaagc tataccagca tgtccgctcc tggctccctg 1920 cctatgccac acctcatttc atccgtatcc aggattccct ggagatcaca aacacctaca 1980 agctggtaaa gtcacggctg gtgcgtgagg gttttgatgt ggggatcatt gctgaccccc 2040 tctacatact ggacaacaag gcccagacct tccggagtct gatgccagat gtgtaccagg 2100 ctgtgtgtga aggaacctgg aatctctgac cacctagcca actggaaggc aatccaaaag 2160 tgtagagatt gacactagtc agcttcacaa agttgtccgg gttccagatg cccatggccc 2220 agtagtactt agagaataaa cttgaatgtg tatacaaaaa aaaaaaaaaa aaaaaaa 2277 73 689 PRT Mus musculus 73 Met Gly Ile Trp Lys Lys Leu Thr Leu Leu Leu Leu Leu Leu Leu Leu 1 5 10 15 Val Gly Leu Gly Gln Pro Pro Trp Pro Ala Ala Met Ala Leu Ala Leu 20 25 30 Arg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val Leu Leu Gly Leu Ala 35 40 45 Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met Pro His Trp Leu Ser 50 55 60 Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu Pro Leu Gln Pro Pro 65 70 75 80 Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala Phe Thr Phe Lys Met 85 90 95 Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu Asn Lys His Pro Pro 100 105 110 Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala Leu Ala Trp Pro Asp 115 120 125 Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly Ser Ser Ile Thr Asn 130 135 140 Ser Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala Trp Val Leu Lys Ala 145 150 155 160 Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg Asp Ala Ala Ala Ile 165 170 175 Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu Ser Val Phe Leu Gly 180 185 190 Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile Asn Pro His Ser Arg 195 200 205 Gly Met Pro Leu Leu His Ser Val Arg Ser Ser Gly Ala Ser Val Leu 210 215 220 Ile Val Asp Pro Asp Leu Gln Glu Asn Leu Glu Glu Val Leu Pro Lys 225 230 235 240 Leu Leu Ala Glu Asn Ile His Cys Phe Tyr Leu Gly His Ser Ser Pro 245 250 255 Thr Pro Gly Val Glu Ala Leu Gly Ala Ser Leu Asp Ala Ala Pro Ser 260 265 270 Asp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile Lys Trp Lys Ser Pro 275 280 285 Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Pro Ala 290 295 300 Ile Leu Ser His Glu Arg Val Ile Gln Val Ser Asn Val Leu Ser Phe 305 310 315 320 Cys Gly Cys Arg Ala Asp Asp Val Val Tyr Asp Val Leu Pro Leu Tyr 325 330 335 His Thr Ile Gly Leu Val Leu Gly Phe Leu Gly Cys Leu Gln Val Gly 340 345 350 Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala Ser Arg Phe Trp Ala 355 360 365 Glu Cys Arg Gln His Gly Val Thr Val Ile Leu Tyr Val Gly Glu Ile 370 375 380 Leu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro Glu Asp Lys Ile His 385 390 395 400 Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg Ala Asn Val Trp Lys 405 410 415 Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile Trp Glu Phe Tyr Gly 420 425 430 Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr Val Gly His Cys Gly 435 440 445 Ala Val Gly Arg Thr Ser Cys Ile Leu Arg Met Leu Thr Pro Phe Glu 450 455 460 Leu Val Gln Phe Asp Ile Glu Thr Ala Glu Pro Leu Arg Asp Lys Gln 465 470 475 480 Gly Phe Cys Ile Pro Val Glu Pro Gly Lys Pro Gly Leu Leu Leu Thr 485 490 495 Lys Val Arg Lys Asn Gln Pro Phe Leu Gly Tyr Arg Gly Ser Gln Ala 500 505 510 Glu Ser Asn Arg Lys Leu Val Ala Asn Val Arg Arg Val Gly Asp Leu 515 520 525 Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp Gln Glu Gly Phe Phe 530 535 540 Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn 545 550 555 560 Val Ser Thr Gly Glu Val Glu Cys Val Leu Ser Ser Leu Asp Phe Leu 565 570 575 Glu Glu Val Asn Val Tyr Gly Val Pro Val Pro Gly Cys Glu Gly Lys 580 585 590 Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly Lys Thr Phe Asp Gly 595 600 605 Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu Pro Ala Tyr Ala Thr 610 615 620 Pro His Phe Ile Arg Ile Gln Asp Ser Leu Glu Ile Thr Asn Thr Tyr 625 630 635 640 Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly Phe Asp Val Gly Ile 645 650 655 Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys Ala Gln Thr Phe Arg 660 665 670 Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys Glu Gly Thr Trp Asn 675 680 685 Leu 74 2221 DNA Drosophila melanogaster 74 gctctctggg cctatatcaa gctgctgagg tacacgaagc gccatgagcg gctcaactac 60 acggtggcgg acgtcttcga acgaaatgtt caggcccatc cggacaaggt ggctgtggtc 120 agtgagacgc aacgctggac cttccgtcag gtgaacgagc atgcgaacaa ggtggccaat 180 gtgctgcagg ctcagggcta caaaaagggc gatgtggtgg ccctgttgct ggagaaccgc 240 gccgagtacg tggccacctg gctgggtctc tccaagatcg gtgtgatcac accgctgatc 300 aacacgaatc tgcgcggtcc ctccctgctg cacagcatca cggtggccca ttgctcggct 360 ctcatttacg gcgaggactt cctggaagct gtcaccgacg tggccaagga tctgccagcg 420 aacctcacac tcttccagtt caacaacgag aacaacaaca gcgagacgga aaagaacata 480 ccgcaggcca agaatctgaa cgcgctgctg accacggcca gctatgagaa gcctaacaag 540 acgcaggtta accaccacga caagctggtc tacatctaca cctccggcac cacaggattg 600 ccaaaggctg cggttatctc tcactcccgt tatctgttta tcgctgctgg catccactac 660 accatgggtt tccaggagga ggacatcttc tacacgccct tgcctttgta ccacaccgct 720 ggtggcatta tgtgcatggg tcagtcggtg ctctttggct ccacggtctc cattcgcaag 780 aagttctcgg catccaacta tttcgccgac tgcgccaagt ataatgcaac tattggtcag 840 tatatcggtg agatggctcg ctacattcta gctacgaaac cctcggaata cgaccagaaa 900 caccgagtgc gtctggtctt tggaaacgga ctgcgaccgc agatttggcc acagtttgtg 960 cagcgcttca acattgccaa ggttggcgag ttctacggcg ccaccgaggg taatgcgaac 1020 atcatgaatc atgacaacac ggtgggcgcc atcggctttg tgtcgcgcat cctgcccaag 1080 atctacccaa tctcgatcat tcgcgccgat ccggacaccg gagagcccat tagagatagg 1140 aatggcctat gccaactgtg cgctcccaac gagccaggcg tattcatcgg caagatcgtc 1200 aaaggaaatc cttctcgcga attcctcgga tacgtcgatg aaaaggcctc cgcgaagaag 1260 attgttaagg atgtgttcaa gcatggcgat atggctttca tctccggaga tctgctggtt 1320 gccgacgaga agggttatct gtacttcaag gatcgcaccg gtgacacctt ccgctggaag 1380 ggcgagaatg tttccaccag cgaggtggag gcgcaagtca gcaatgtggc cggttacaag 1440 gataccgtcg tttacggcgt aaccattccg cacaccgagg gaagggccgg catggccgcc 1500 atctatgatc cggagcgaga attggacctc gacgtcttcg ccgctagctt ggccaaggtg 1560 ctgcccgcgt acgctcgtcc ccagatcatt cgattgctca ccaaggtgga cctgactgga 1620 acctttaagc tgcgcaaggt agacctgcag aaggagggct acgatccgaa cgcgatcaag 1680 gacgcgctgt actaccagac ttccaagggt cggtacgagc tgctcacgcc ccaggtttac 1740 gaccaggtgc agcgcaacga aatccgcttc taagagctgc aatagagttg tgtctgaacc 1800 ttgccttttg cccaatatgc tgttaattag tttgtaaggc taagtgtagt agaggaaaat 1860 cgggggaaat cggcagcaaa gatcattcag cctaggagag atgcatccga agcacatttc 1920 catgtcaaca atgcactttt gtatatcgta agcatatata tatcgtatat cgtaaacgta 1980 gttgtatctg catttgtgta gatgatagcc tcctatacgc atttcaattg tttttagcgt 2040 gctaaagaac cttgttaaat gcaatttcag ctattgttta gtcagtttta gtggcattta 2100 cacttccatt ctcgttgcgt ttcgtttttg cctgtacata tgagaagctc tgatgttttt 2160 gtatcaaata aagttttttc cttcaccacg gaccacgtga aaaaaaaaaa aaaaaaaaaa 2220 a 2221 75 590 PRT Drosophila melanogaster 75 Ala Leu Trp Ala Tyr Ile Lys Leu Leu Arg Tyr Thr Lys Arg His Glu 1 5 10 15 Arg Leu Asn Tyr Thr Val Ala Asp Val Phe Glu Arg Asn Val Gln Ala 20 25 30 His Pro Asp Lys Val Ala Val Val Ser Glu Thr Gln Arg Trp Thr Phe 35 40 45 Arg Gln Val Asn Glu His Ala Asn Lys Val Ala Asn Val Leu Gln Ala 50 55 60 Gln Gly Tyr Lys Lys Gly Asp Val Val Ala Leu Leu Leu Glu Asn Arg 65 70 75 80 Ala Glu Tyr Val Ala Thr Trp Leu Gly Leu Ser Lys Ile Gly Val Ile 85 90 95 Thr Pro Leu Ile Asn Thr Asn Leu Arg Gly Pro Ser Leu Leu His Ser 100 105 110 Ile Thr Val Ala His Cys Ser Ala Leu Ile Tyr Gly Glu Asp Phe Leu 115 120 125 Glu Ala Val Thr Asp Val Ala Lys Asp Leu Pro Ala Asn Leu Thr Leu 130 135 140 Phe Gln Phe Asn Asn Glu Asn Asn Asn Ser Glu Thr Glu Lys Asn Ile 145 150 155 160 Pro Gln Ala Lys Asn Leu Asn Ala Leu Leu Thr Thr Ala Ser Tyr Glu 165 170 175 Lys Pro Asn Lys Thr Gln Val Asn His His Asp Lys Leu Val Tyr Ile 180 185 190 Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser His 195 200 205 Ser Arg Tyr Leu Phe Ile Ala Ala Gly Ile His Tyr Thr Met Gly Phe 210 215 220 Gln Glu Glu Asp Ile Phe Tyr Thr Pro Leu Pro Leu Tyr His Thr Ala 225 230 235 240 Gly Gly Ile Met Cys Met Gly Gln Ser Val Leu Phe Gly Ser Thr Val 245 250 255 Ser Ile Arg Lys Lys Phe Ser Ala Ser Asn Tyr Phe Ala Asp Cys Ala 260 265 270 Lys Tyr Asn Ala Thr Ile Gly Gln Tyr Ile Gly Glu Met Ala Arg Tyr 275 280 285 Ile Leu Ala Thr Lys Pro Ser Glu Tyr Asp Gln Lys His Arg Val Arg 290 295 300 Leu Val Phe Gly Asn Gly Leu Arg Pro Gln Ile Trp Pro Gln Phe Val 305 310 315 320 Gln Arg Phe Asn Ile Ala Lys Val Gly Glu Phe Tyr Gly Ala Thr Glu 325 330 335 Gly Asn Ala Asn Ile Met Asn His Asp Asn Thr Val Gly Ala Ile Gly 340 345 350 Phe Val Ser Arg Ile Leu Pro Lys Ile Tyr Pro Ile Ser Ile Ile Arg 355 360 365 Ala Asp Pro Asp Thr Gly Glu Pro Ile Arg Asp Arg Asn Gly Leu Cys 370 375 380 Gln Leu Cys Ala Pro Asn Glu Pro Gly Val Phe Ile Gly Lys Ile Val 385 390 395 400 Lys Gly Asn Pro Ser Arg Glu Phe Leu Gly Tyr Val Asp Glu Lys Ala 405 410 415 Ser Ala Lys Lys Ile Val Lys Asp Val Phe Lys His Gly Asp Met Ala 420 425 430 Phe Ile Ser Gly Asp Leu Leu Val Ala Asp Glu Lys Gly Tyr Leu Tyr 435 440 445 Phe Lys Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val 450 455 460 Ser Thr Ser Glu Val Glu Ala Gln Val Ser Asn Val Ala Gly Tyr Lys 465 470 475 480 Asp Thr Val Val Tyr Gly Val Thr Ile Pro His Thr Glu Gly Arg Ala 485 490 495 Gly Met Ala Ala Ile Tyr Asp Pro Glu Arg Glu Leu Asp Leu Asp Val 500 505 510 Phe Ala Ala Ser Leu Ala Lys Val Leu Pro Ala Tyr Ala Arg Pro Gln 515 520 525 Ile Ile Arg Leu Leu Thr Lys Val Asp Leu Thr Gly Thr Phe Lys Leu 530 535 540 Arg Lys Val Asp Leu Gln Lys Glu Gly Tyr Asp Pro Asn Ala Ile Lys 545 550 555 560 Asp Ala Leu Tyr Tyr Gln Thr Ser Lys Gly Arg Tyr Glu Leu Leu Thr 565 570 575 Pro Gln Val Tyr Asp Gln Val Gln Arg Asn Glu Ile Arg Phe 580 585 590 76 173 DNA Danio rerio 76 agtgtagata ccacaggaac gtttaaaatc cagaagacca gactgcaaag ggaaggatac 60 gatccacggc tcacaactga ccagatctac ttcctaaact ccagagcagg gcgttacgag 120 cttgtcaacg aggagctgta caatgcattt gaacaagggc aggatttccc ttt 173 77 57 PRT Danio rerio 77 Ser Val Asp Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln 1 5 10 15 Arg Glu Gly Tyr Asp Pro Arg Leu Thr Thr Asp Gln Ile Tyr Phe Leu 20 25 30 Asn Ser Arg Ala Gly Arg Tyr Glu Leu Val Asn Glu Glu Leu Tyr Asn 35 40 45 Ala Phe Glu Gln Gly Gln Asp Phe Pro 50 55 78 1953 DNA Caenorhabditis elegans 78 atgaagctgg aggagcttgt gacagttatg cttctcacag tggctgtcat tgctcagaat 60 cttccgattg gagtaatatt ggctggagtt cttattttat acatcacagt ggttcatgga 120 gatttcattt atagaagtta tcttacgttg aatagggatt taacaggatt ggctctaatt 180 attgaagtca aaatcgacct atggtggagg ttgcatcaga ataaaggaat ccatgaactg 240 tttttggata ttgtgaaaaa gaatccaaat aagccggcga tgattgacat cgagacgaat 300 acaacagaaa catacgcaga gttcaatgca cattgtaata gatatgccaa ttatttccag 360 ggtcttggct atcgatccgg agacgttgtc gccttgtaca tggagaactc ggtcgagttt 420 gtggccgcgt ggatgggact cgcaaaaatc ggagttgtaa cggcttggat caactcgaat 480 ttgaaaagag agcaacttgt tcattgtatc actgcgagca agacaaaggc gattatcaca 540 agtgtaacac ttcagaatat tatgcttgat gctatcgatc agaagctgtt tgatgttgag 600 ggaattgagg tttactctgt cggagagccc aagaagaatt ctggattcaa gaatctcaag 660 aagaagttgg atgctcaaat tactacggaa ccaaagaccc ttgacatagt agattttaaa 720 agtattcttt gcttcatcta tacaagtggt actactggaa tgccaaaagc cgctgtcatg 780 aagcacttca gatattactc gattgccgtt ggagccgcaa aatcattcgg aatccgccct 840 tctgatcgta tgtacgtctc gatgccaatt tatcacactg cagctggaat tcttggagtt 900 gggcaagctc tgttgggtgg atcatcgtgt gtcattagaa aaaaattctc ggctagcaac 960 ttttggaggg attgtgtaaa gtatgattgt acagtttcac aatacattgg agagatttgt 1020 cggtacttgt tggctcagcc agttgtggaa gaggaatcca ggcatagaat gagattgttg 1080 gttggaaacg gactccgtgc tgaaatctgg caaccatttg tagatcgatt ccgtgtcaga 1140 attggagaac tttatggttc aactgaagga acttcatctc tcgtgaacat tgacggacat 1200 gtcggagctt gcggattctt gccaatatcc ccattaacaa agaaaatgca tccggttcga 1260 ttaattaagg ttgatgatgt cactggagaa gcaatccgaa cttccgatgg actttgcatt 1320 gcatgtaatc caggagagtc tggagcaatg gtgtcgacga tcagaaaaaa taatccatta 1380 ttgcaattcg agggatatct gaataagaag gaaacgaata aaaagattat cagagatgtc 1440 ttcgcaaagg gagatagttg ctttttgact ggagatcttc ttcattggga tcgtcttggt 1500 tatgtatatt tcaaggatcg tactggagat actttccgtt ggaagggaga gaatgtgtcg 1560 actactgaag tcgaggcaat tcttcatcca attactggat tgtctgatgc aactgtttat 1620 ggtgtagagg ttcctcaaag agagggaaga gttggaatgg cgtcagttgt tcgagttgta 1680 tcgcatgagg aagatgaaac tcaatttgtt catagagttg gagcaagact tgcctcttcg 1740 cttaccagct acgcgattcc tcagtttatg cgaatttgtc aggatgttga gaaaacaggt 1800 acattcaaac ttgtgaagac gaatctacaa cgattaggta tcatggatgc tccttcagat 1860 tcaatttaca tctacaattc tgaaaatcgc aattttgtgc cgttcgacaa tgatttgagg 1920 tgcaaggtct cactgggaag ttatccattt taa 1953 79 650 PRT Caenorhabditis elegans 79 Met Lys Leu Glu Glu Leu Val Thr Val Met Leu Leu Thr Val Ala Val 1 5 10 15 Ile Ala Gln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly Val Leu Ile 20 25 30 Leu Tyr Ile Thr Val Val His Gly Asp Phe Ile Tyr Arg Ser Tyr Leu 35 40 45 Thr Leu Asn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile Glu Val Lys 50 55 60 Ile Asp Leu Trp Trp Arg Leu His Gln Asn Lys Gly Ile His Glu Leu 65 70 75 80 Phe Leu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro Ala Met Ile Asp 85 90 95 Ile Glu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe Asn Ala His Cys 100 105 110 Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly Tyr Arg Ser Gly Asp 115 120 125 Val Val Ala Leu Tyr Met Glu Asn Ser Val Glu Phe Val Ala Ala Trp 130 135 140 Met Gly Leu Ala Lys Ile Gly Val Val Thr Ala Trp Ile Asn Ser Asn 145 150 155 160 Leu Lys Arg Glu Gln Leu Val His Cys Ile Thr Ala Ser Lys Thr Lys 165 170 175 Ala Ile Ile Thr Ser Val Thr Leu Gln Asn Ile Met Leu Asp Ala Ile 180 185 190 Asp Gln Lys Leu Phe Asp Val Glu Gly Ile Glu Val Tyr Ser Val Gly 195 200 205 Glu Pro Lys Lys Asn Ser Gly Phe Lys Asn Leu Lys Lys Lys Leu Asp 210 215 220 Ala Gln Ile Thr Thr Glu Pro Lys Thr Leu Asp Ile Val Asp Phe Lys 225 230 235 240 Ser Ile Leu Cys Phe Ile Tyr Thr Ser Gly Thr Thr Gly Met Pro Lys 245 250 255 Ala Ala Val Met Lys His Phe Arg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270 Ala Lys Ser Phe Gly Ile Arg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280 285 Pro Ile Tyr His Thr Ala Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290 295 300 Leu Gly Gly Ser Ser Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn 305 310 315 320 Phe Trp Arg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser Gln Tyr Ile 325 330 335 Gly Glu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val Val Glu Glu Glu 340 345 350 Ser Arg His Arg Met Arg Leu Leu Val Gly Asn Gly Leu Arg Ala Glu 355 360 365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg Val Arg Ile Gly Glu Leu 370 375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser Leu Val Asn Ile Asp Gly His 385 390 395 400 Val Gly Ala Cys Gly Phe Leu Pro Ile Ser Pro Leu Thr Lys Lys Met 405 410 415 His Pro Val Arg Leu Ile Lys Val Asp Asp Val Thr Gly Glu Ala Ile 420 425 430 Arg Thr Ser Asp Gly Leu Cys Ile Ala Cys Asn Pro Gly Glu Ser Gly 435 440 445 Ala Met Val Ser Thr Ile Arg Lys Asn Asn Pro Leu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu Asn Lys Lys Glu Thr Asn Lys Lys Ile Ile Arg Asp Val 465 470 475 480 Phe Ala Lys Gly Asp Ser Cys Phe Leu Thr Gly Asp Leu Leu His Trp 485 490 495 Asp Arg Leu Gly Tyr Val Tyr Phe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510 Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520 525 His Pro Ile Thr Gly Leu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530 535 540 Pro Gln Arg Glu Gly Arg Val Gly Met Ala Ser Val Val Arg Val Val 545 550 555 560 Ser His Glu Glu Asp Glu Thr Gln Phe Val His Arg Val Gly Ala Arg 565 570 575 Leu Ala Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln Phe Met Arg Ile 580 585 590 Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys Leu Val Lys Thr Asn 595 600 605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro Ser Asp Ser Ile Tyr Ile 610 615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val Pro Phe Asp Asn Asp Leu Arg 625 630 635 640 Cys Lys Val Ser Leu Gly Ser Tyr Pro Phe 645 650 80 1968 DNA Caenorhabditis elegans 80 atgagggaaa tgccggacag tcccaagttt gcgttagtca cgtttgttgt gtatgcagtg 60 gttttgtaca atgtcaacag cgttttctgg aaatttgtat tcatcggata tgttgtattt 120 aggctgcttc gcactgattt tggaagaaga gcacttgcca cgttacctag agattttgcg 180 ggactgaagc tcttaatatc ggttaagtcg acaattcgtg gcttgttcaa gaaagatcgc 240 ccaattcatg aaatcttttt gaatcaggtg aaacagcatc caaacaaagt ggcgattatt 300 gaaattgaaa gtggtaggca gttgacgtat caagaattga atgcgttagc taatcagtat 360 gctaaccttt acgtgagtga aggttacaaa atgggcgacg ttgtcgcttt gtttatggaa 420 aatagcatcg acttctttgc aatttggctg ggactttcca agattggagt cgtgtcggcg 480 ttcatcaact caaacttgaa gttggagcca ttggcacatt cgattaatgt ttcgaagtgc 540 aaatcatgca ttaccaatat caatctgttg ccgatgttca aagccgctcg tgaaaagaat 600 ctgatcagtg acgagatcca cgtgtttctg gctggaactc aggttgatgg acgtcataga 660 agtcttcagc aagatctcca tcttttctct gaggatgaac ctccagttat agacggactc 720 aattttagaa gcgttctgtg ttatatttac acttccggta ctaccggaaa tccaaagcca 780 gccgtcatta aacacttccg ttacttctgg attgcgatgg gagcaggaaa agcatttgga 840 attaataagt cagacgttgt gtacattacg atgccaatgt atcactctgc cgccggtatc 900 atgggtattg gatcattaat tgcattcggg tcgaccgctg ttattaggaa aaagttttcg 960 gcaagcaact tctggaaaga ttgcgtcaag tacaacgtca cagcgacaca gtacattgga 1020 gaaatctgca ggtatcttct ggcagcgaat ccatgtcctg aagagaaaca acacaacgtg 1080 cgattgatgt ggggaaatgg tttgagagga caaatttgga aagagtttgt aggaagattt 1140 ggaattaaga aaattggaga gttgtacggc tcaacagaag gaaactccaa tattgttaac 1200 gtggataacc atgttggagc ttgtggattc atgccaattt atccccatat tggatccctc 1260 tacccagttc gacttattaa ggttgataga gccactggag agcttgaacg tgataagaac 1320 ggactctgtg tgccgtgtgt gcctggtgaa actggggaaa tggttggcgt tatcaaggag 1380 aaagatattc ttctaaagtt cgaaggatat gtcagcgaag gggatactgc aaagaaaatc 1440 tacagagatg tgttcaagca tggagataag gtgtttgcaa gtggagatat tcttcattgg 1500 gatgatcttg gatacttgta ctttgtggac cgttgtggag acactttccg ttggaaaggg 1560 gagaacgtgt caactactga agttgaggga attcttcagc ctgtgatgga tgtggaagat 1620 gcaactgttt atggagtcac tgtcggtaaa atggaggggc gtgccggaat ggctggtatt 1680 gtcgtcaagg atggaacgga tgttgagaaa ttcatcgccg atattacttc tcgactgacc 1740 gaaaatctgg cgtcttacgc aatccctgtt ttcattcggc tgtgcaagga agttgatcga 1800 accggaacct tcaaactcaa gaagactgat cttcaaaaac aaggttacga cctggttgct 1860 tgtaaaggag acccaattta ctactggtca gctgcagaaa aatcctacaa accactgact 1920 gacaaaatgc aacaggatat tgacactggt gtttatgatc gcatttaa 1968 81 655 PRT Caenorhabditis elegans 81 Met Arg Glu Met Pro Asp Ser Pro Lys Phe Ala Leu Val Thr Phe Val 1 5 10 15 Val Tyr Ala Val Val Leu Tyr Asn Val Asn Ser Val Phe Trp Lys Phe 20 25 30 Val Phe Ile Gly Tyr Val Val Phe Arg Leu Leu Arg Thr Asp Phe Gly 35 40 45 Arg Arg Ala Leu Ala Thr Leu Pro Arg Asp Phe Ala Gly Leu Lys Leu 50 55 60 Leu Ile Ser Val Lys Ser Thr Ile Arg Gly Leu Phe Lys Lys Asp Arg 65 70 75 80 Pro Ile His Glu Ile Phe Leu Asn Gln Val Lys Gln His Pro Asn Lys 85 90 95 Val Ala Ile Ile Glu Ile Glu Ser Gly Arg Gln Leu Thr Tyr Gln Glu 100 105 110 Leu Asn Ala Leu Ala Asn Gln Tyr Ala Asn Leu Tyr Val Ser Glu Gly 115 120 125 Tyr Lys Met Gly Asp Val Val Ala Leu Phe Met Glu Asn Ser Ile Asp 130 135 140 Phe Phe Ala Ile Trp Leu Gly Leu Ser Lys Ile Gly Val Val Ser Ala 145 150 155 160 Phe Ile Asn Ser Asn Leu Lys Leu Glu Pro Leu Ala His Ser Ile Asn 165 170 175 Val Ser Lys Cys Lys Ser Cys Ile Thr Asn Ile Asn Leu Leu Pro Met 180 185 190 Phe Lys Ala Ala Arg Glu Lys Asn Leu Ile Ser Asp Glu Ile His Val 195 200 205 Phe Leu Ala Gly Thr Gln Val Asp Gly Arg His Arg Ser Leu Gln Gln 210 215 220 Asp Leu His Leu Phe Ser Glu Asp Glu Pro Pro Val Ile Asp Gly Leu 225 230 235 240 Asn Phe Arg Ser Val Leu Cys Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 245 250 255 Asn Pro Lys Pro Ala Val Ile Lys His Phe Arg Tyr Phe Trp Ile Ala 260 265 270 Met Gly Ala Gly Lys Ala Phe Gly Ile Asn Lys Ser Asp Val Val Tyr 275 280 285 Ile Thr Met Pro Met Tyr His Ser Ala Ala Gly Ile Met Gly Ile Gly 290 295 300 Ser Leu Ile Ala Phe Gly Ser Thr Ala Val Ile Arg Lys Lys Phe Ser 305 310 315 320 Ala Ser Asn Phe Trp Lys Asp Cys Val Lys Tyr Asn Val Thr Ala Thr 325 330 335 Gln Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu Ala Ala Asn Pro Cys 340 345 350 Pro Glu Glu Lys Gln His Asn Val Arg Leu Met Trp Gly Asn Gly Leu 355 360 365 Arg Gly Gln Ile Trp Lys Glu Phe Val Gly Arg Phe Gly Ile Lys Lys 370 375 380 Ile Gly Glu Leu Tyr Gly Ser Thr Glu Gly Asn Ser Asn Ile Val Asn 385 390 395 400 Val Asp Asn His Val Gly Ala Cys Gly Phe Met Pro Ile Tyr Pro His 405 410 415 Ile Gly Ser Leu Tyr Pro Val Arg Leu Ile Lys Val Asp Arg Ala Thr 420 425 430 Gly Glu Leu Glu Arg Asp Lys Asn Gly Leu Cys Val Pro Cys Val Pro 435 440 445 Gly Glu Thr Gly Glu Met Val Gly Val Ile Lys Glu Lys Asp Ile Leu 450 455 460 Leu Lys Phe Glu Gly Tyr Val Ser Glu Gly Asp Thr Ala Lys Lys Ile 465 470 475 480 Tyr Arg Asp Val Phe Lys His Gly Asp Lys Val Phe Ala Ser Gly Asp 485 490 495 Ile Leu His Trp Asp Asp Leu Gly Tyr Leu Tyr Phe Val Asp Arg Cys 500 505 510 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 515 520 525 Glu Gly Ile Leu Gln Pro Val Met Asp Val Glu Asp Ala Thr Val Tyr 530 535 540 Gly Val Thr Val Gly Lys Met Glu Gly Arg Ala Gly Met Ala Gly Ile 545 550 555 560 Val Val Lys Asp Gly Thr Asp Val Glu Lys Phe Ile Ala Asp Ile Thr 565 570 575 Ser Arg Leu Thr Glu Asn Leu Ala Ser Tyr Ala Ile Pro Val Phe Ile 580 585 590 Arg Leu Cys Lys Glu Val Asp Arg Thr Gly Thr Phe Lys Leu Lys Lys 595 600 605 Thr Asp Leu Gln Lys Gln Gly Tyr Asp Leu Val Ala Cys Lys Gly Asp 610 615 620 Pro Ile Tyr Tyr Trp Ser Ala Ala Glu Lys Ser Tyr Lys Pro Leu Thr 625 630 635 640 Asp Lys Met Gln Gln Asp Ile Asp Thr Gly Val Tyr Asp Arg Ile 645 650 655 82 1932 DNA Cochliobolu heterostrophus 82 atggcgtgta tgcatcaggc tcagctatac aatgatctag aggaattgct aactggtcca 60 tcagtaccca tcgttgctgg agctgctgga gctgcagctc tcactgccta cattaacgcc 120 aaataccaca tagcccatga tctcaagacc ctcggtggtg gattgacaca atcgtccgaa 180 gcgattgatt tcataaaccg ccgcgtcgca caaaagcgcg tcctcacgca ccacatcttc 240 caggagcagg tccaaaaaca atcaaatcat ccctttctta tctttgaggg caagacatgg 300 tcttacaagg agttctctga ggcatacacg agggtcgcga actggctgat tgatgagctg 360 gacgtacaag taggggagat ggtcgcaatt gatggcggaa atagtgcaga gcacctgatg 420 ctttggcttg cacttgatgc aatcggtgcg gctacgagtt ttttgaactg gaacctgaca 480 ggggcagggt taattcattg cataaagcta tgcgaatgtc gattcgttat cgcagacatc 540 gatattaaag cgaacattga accgtgccgt ggcgaactgg aggagacggg catcaacatt 600 cactactatg acccatcctt catctcatcg ctaccgaata acacgccaat tcccgacagc 660 cgcactgaga acattgaatt agattcagta cgaggactga tatacacatc tggaaccact 720 ggtctaccta aaggcgtgtt tataagcact ggccgcgagc ttaggactga ctggtcgatt 780 tcaaagtatc taaatctcaa gcccacggat cgaatgtata catgtatgcc gctctaccat 840 gccgctgcac acagcctctg tacagcatca gttattcatg gtggaggtac cgtggtattg 900 agcaggaaat tctcacacaa gaagttctgg cctgaagttg tggcttcgga agcaaatatc 960 attcagtacg ttggtgaatt aggtcgatat ctcctgaatg gtccaaagag tccttacgac 1020 agggcccata aagtccagat ggcgtggggc aatggcatgc gtccagacgt gtgggaagcg 1080 tttcgtgaac gcttcaacat accaattatt catgagctct atgccgcaac cgatgggctc 1140 gggtcaatga ccaatcgtaa cgcgggccct tttacagcaa actgtattgc gctgcgaggg 1200 ctgatctggc actggaaatt tcgaaatcag gaagtgctgg tcaagatgga tctcgatact 1260 gatgagatca tgagagatcg caatgggttt gcgatacgat gcgctgtcaa tgaacctgga 1320 cagatgcttt ttcggctgac acccgaaact ctggctggtg caccaagcta ctacaacaac 1380 gaaacggcca cacagagcag gcggattaca gatgtgtttc aaaagggtga cctgtggttc 1440 aagtccggtg acatgctacg gcaagacgcc gaaggccgcg tctactttgt cgatcgacta 1500 ggcgatacgt tccgctggaa atccgaaaac gtttctacca atgaagtcgc ggacgtgatg 1560 ggcacatttc ctcagattgc tgaaacgaat gtatacggtg tccttgtgcc gggtaacgat 1620 ggtcgagtgc gcagcctcaa ttgtcatggc agacggcgtg acagagtcga cattcgcttc 1680 gctgcccttg caaagcacgc ccgagatcgg ttaccgggtt atgctgtacc actgtttctg 1740 agggtaactc cagcacttga atatacgggc acattaaaga ttcagaaagg acgcctcaag 1800 caggaaggta tagacccaga taagatttcc ggcgaagata agttatactg gctgccgcct 1860 ggtagcgata tatatttacc atttggaaag atggagtggc agggaattgt agataagcgt 1920 atacggctgt ga 1932 83 643 PRT Cochliobolu heterostrophus 83 Met Ala Cys Met His Gln Ala Gln Leu Tyr Asn Asp Leu Glu Glu Leu 1 5 10 15 Leu Thr Gly Pro Ser Val Pro Ile Val Ala Gly Ala Ala Gly Ala Ala 20 25 30 Ala Leu Thr Ala Tyr Ile Asn Ala Lys Tyr His Ile Ala His Asp Leu 35 40 45 Lys Thr Leu Gly Gly Gly Leu Thr Gln Ser Ser Glu Ala Ile Asp Phe 50 55 60 Ile Asn Arg Arg Val Ala Gln Lys Arg Val Leu Thr His His Ile Phe 65 70 75 80 Gln Glu Gln Val Gln Lys Gln Ser Asn His Pro Phe Leu Ile Phe Glu 85 90 95 Gly Lys Thr Trp Ser Tyr Lys Glu Phe Ser Glu Ala Tyr Thr Arg Val 100 105 110 Ala Asn Trp Leu Ile Asp Glu Leu Asp Val Gln Val Gly Glu Met Val 115 120 125 Ala Ile Asp Gly Gly Asn Ser Ala Glu His Leu Met Leu Trp Leu Ala 130 135 140 Leu Asp Ala Ile Gly Ala Ala Thr Ser Phe Leu Asn Trp Asn Leu Thr 145 150 155 160 Gly Ala Gly Leu Ile His Cys Ile Lys Leu Cys Glu Cys Arg Phe Val 165 170 175 Ile Ala Asp Ile Asp Ile Lys Ala Asn Ile Glu Pro Cys Arg Gly Glu 180 185 190 Leu Glu Glu Thr Gly Ile Asn Ile His Tyr Tyr Asp Pro Ser Phe Ile 195 200 205 Ser Ser Leu Pro Asn Asn Thr Pro Ile Pro Asp Ser Arg Thr Glu Asn 210 215 220 Ile Glu Leu Asp Ser Val Arg Gly Leu Ile Tyr Thr Ser Gly Thr Thr 225 230 235 240 Gly Leu Pro Lys Gly Val Phe Ile Ser Thr Gly Arg Glu Leu Arg Thr 245 250 255 Asp Trp Ser Ile Ser Lys Tyr Leu Asn Leu Lys Pro Thr Asp Arg Met 260 265 270 Tyr Thr Cys Met Pro Leu Tyr His Ala Ala Ala His Ser Leu Cys Thr 275 280 285 Ala Ser Val Ile His Gly Gly Gly Thr Val Val Leu Ser Arg Lys Phe 290 295 300 Ser His Lys Lys Phe Trp Pro Glu Val Val Ala Ser Glu Ala Asn Ile 305 310 315 320 Ile Gln Tyr Val Gly Glu Leu Gly Arg Tyr Leu Leu Asn Gly Pro Lys 325 330 335 Ser Pro Tyr Asp Arg Ala His Lys Val Gln Met Ala Trp Gly Asn Gly 340 345 350 Met Arg Pro Asp Val Trp Glu Ala Phe Arg Glu Arg Phe Asn Ile Pro 355 360 365 Ile Ile His Glu Leu Tyr Ala Ala Thr Asp Gly Leu Gly Ser Met Thr 370 375 380 Asn Arg Asn Ala Gly Pro Phe Thr Ala Asn Cys Ile Ala Leu Arg Gly 385 390 395 400 Leu Ile Trp His Trp Lys Phe Arg Asn Gln Glu Val Leu Val Lys Met 405 410 415 Asp Leu Asp Thr Asp Glu Ile Met Arg Asp Arg Asn Gly Phe Ala Ile 420 425 430 Arg Cys Ala Val Asn Glu Pro Gly Gln Met Leu Phe Arg Leu Thr Pro 435 440 445 Glu Thr Leu Ala Gly Ala Pro Ser Tyr Tyr Asn Asn Glu Thr Ala Thr 450 455 460 Gln Ser Arg Arg Ile Thr Asp Val Phe Gln Lys Gly Asp Leu Trp Phe 465 470 475 480 Lys Ser Gly Asp Met Leu Arg Gln Asp Ala Glu Gly Arg Val Tyr Phe 485 490 495 Val Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Ser Glu Asn Val Ser 500 505 510 Thr Asn Glu Val Ala Asp Val Met Gly Thr Phe Pro Gln Ile Ala Glu 515 520 525 Thr Asn Val Tyr Gly Val Leu Val Pro Gly Asn Asp Gly Arg Val Arg 530 535 540 Ser Leu Asn Cys His Gly Arg Arg Arg Asp Arg Val Asp Ile Arg Phe 545 550 555 560 Ala Ala Leu Ala Lys His Ala Arg Asp Arg Leu Pro Gly Tyr Ala Val 565 570 575 Pro Leu Phe Leu Arg Val Thr Pro Ala Leu Glu Tyr Thr Gly Thr Leu 580 585 590 Lys Ile Gln Lys Gly Arg Leu Lys Gln Glu Gly Ile Asp Pro Asp Lys 595 600 605 Ile Ser Gly Glu Asp Lys Leu Tyr Trp Leu Pro Pro Gly Ser Asp Ile 610 615 620 Tyr Leu Pro Phe Gly Lys Met Glu Trp Gln Gly Ile Val Asp Lys Arg 625 630 635 640 Ile Arg Leu 84 597 DNA Aspergillus nidulans 84 ctttaccatt catcagcttc attctgcatt tttagcttga cggcagccgg gtctacgctg 60 atcatcggcc gcaagttctc cgcgagaaac ttcataaagg aagcgcgcga gaacgacgcc 120 acggtcatcc agtacgtggg tgagaccttg cgatatctgc tcgccacccc cggtgaaacc 180 gatccagtta ctggcgaaga cctggacaaa aagcacaata ttcgagcagt atacggcaac 240 gggctacggc cggatatctg gaaccgcttc aaggagcgct tcaacgtgcc gacggttgcc 300 gaattttatg ctgcaaccga gagcccaggc ggaacatgga actattcaac aaatgacttc 360 actgccggag ccattgggca cactggcgtg cttagtggat ggcttcttgg acgcggcctt 420 actattgtcg aggtggacca ggaatcacag gaaccatggc gcgatcccca aaccgggttc 480 tgcaagccgg tcccgcgagg cgaagcaggc gagctcctgt atgccattga tccggccgac 540 ccgggcgaga ccttccaggg ctactaccgc aactccttta gagcacactg gcggccg 597 85 199 PRT Aspergillus nidulans 85 Leu Tyr His Ser Ser Ala Ser Phe Cys Ile Phe Ser Leu Thr Ala Ala 1 5 10 15 Gly Ser Thr Leu Ile Ile Gly Arg Lys Phe Ser Ala Arg Asn Phe Ile 20 25 30 Lys Glu Ala Arg Glu Asn Asp Ala Thr Val Ile Gln Tyr Val Gly Glu 35 40 45 Thr Leu Arg Tyr Leu Leu Ala Thr Pro Gly Glu Thr Asp Pro Val Thr 50 55 60 Gly Glu Asp Leu Asp Lys Lys His Asn Ile Arg Ala Val Tyr Gly Asn 65 70 75 80 Gly Leu Arg Pro Asp Ile Trp Asn Arg Phe Lys Glu Arg Phe Asn Val 85 90 95 Pro Thr Val Ala Glu Phe Tyr Ala Ala Thr Glu Ser Pro Gly Gly Thr 100 105 110 Trp Asn Tyr Ser Thr Asn Asp Phe Thr Ala Gly Ala Ile Gly His Thr 115 120 125 Gly Val Leu Ser Gly Trp Leu Leu Gly Arg Gly Leu Thr Ile Val Glu 130 135 140 Val Asp Gln Glu Ser Gln Glu Pro Trp Arg Asp Pro Gln Thr Gly Phe 145 150 155 160 Cys Lys Pro Val Pro Arg Gly Glu Ala Gly Glu Leu Leu Tyr Ala Ile 165 170 175 Asp Pro Ala Asp Pro Gly Glu Thr Phe Gln Gly Tyr Tyr Arg Asn Ser 180 185 190 Phe Arg Ala His Trp Arg Pro 195 86 522 DNA Magnaporthe grisea misc_feature (1)...(522) n = A,T,C or G 86 gcaaaggccg acgcgtggct gcggacgggt aacgtgatca gggcggacaa cgaagggcga 60 ctcttcttcc acgaccggat cggagacacg ttccgatgga agggagagac ngtcagcaca 120 caagaggtca gtttggtgct cggacgacac gactcaatca aggaggccaa cgtgtacggc 180 gtgacggtgc cgaaccacga cgggcgggcc ggctgcgctg cgctcacgct atcagacgct 240 ctggcgactg aaaagaagct gggcgatgag ctgctaaagg gattggctac tcactcgtcg 300 acttcgcttc ccaagtttgc ggtgccgcag ttcctacggg tggtgcgcgg cgagatgcag 360 tcaacgggca ccaacaagca acagaagcac gacctgaggg tgcagggtgt agagccgggc 420 aaggtgggcg tagacgaggt gtactggttg cggggaggga catatgtacc attcggaaca 480 gaggattggg atgggttgaa gaagggtctt gtgaagttgt ga 522 87 173 PRT Magnaporthe grisea 87 Ala Lys Ala Asp Ala Trp Leu Arg Thr Gly Asn Val Ile Arg Ala Asp 1 5 10 15 Asn Glu Gly Arg Leu Phe Phe His Asp Arg Ile Gly Asp Thr Phe Arg 20 25 30 Trp Lys Gly Glu Thr Val Ser Thr Gln Glu Val Ser Leu Val Leu Gly 35 40 45 Arg His Asp Ser Ile Lys Glu Ala Asn Val Tyr Gly Val Thr Val Pro 50 55 60 Asn His Asp Gly Arg Ala Gly Cys Ala Ala Leu Thr Leu Ser Asp Ala 65 70 75 80 Leu Ala Thr Glu Lys Lys Leu Gly Asp Glu Leu Leu Lys Gly Leu Ala 85 90 95 Thr His Ser Ser Thr Ser Leu Pro Lys Phe Ala Val Pro Gln Phe Leu 100 105 110 Arg Val Val Arg Gly Glu Met Gln Ser Thr Gly Thr Asn Lys Gln Gln 115 120 125 Lys His Asp Leu Arg Val Gln Gly Val Glu Pro Gly Lys Val Gly Val 130 135 140 Asp Glu Val Tyr Trp Leu Arg Gly Gly Thr Tyr Val Pro Phe Gly Thr 145 150 155 160 Glu Asp Trp Asp Gly Leu Lys Lys Gly Leu Val Lys Leu 165 170 88 1872 DNA Saccharomyces cerevisiae 88 atgtctccca tacaggttgt tgtctttgcc ttgtcaagga ttttcctgct attattcaga 60 cttatcaagc taattataac ccctatccag aaatcactgg gttatctatt tggtaattat 120 tttgatgaat tagaccgtaa atatagatac aaggaggatt ggtatattat tccttacttt 180 ttgaaaagcg tgttttgtta tatcattgat gtgagaagac ataggtttca aaactggtac 240 ttatttatta aacaggtcca acaaaatggt gaccatttag cgattagtta cacccgtccc 300 atggccgaaa agggagaatt tcaactcgaa acctttacgt atattgaaac ttataacata 360 gtgttgagat tgtctcatat tttgcatttt gattataacg ttcaggccgg tgactacgtg 420 gcaatcgatt gtactaataa acctcttttc gtatttttat ggctttcttt gtggaacatt 480 ggggctattc cagctttttt aaactataat actaaaggca ctccgctggt tcactcccta 540 aagatttcca atattacgca ggtatttatt gaccctgatg ccagtaatcc gatcagagaa 600 tcggaagaag aaatcaaaaa cgcacttcct gatgttaaat taaactatct tgaagaacaa 660 gacttaatgc atgaactttt aaattcgcaa tcaccggaat tcttacaaca agacaacgtt 720 aggacaccac taggcttgac cgattttaaa ccctctatgt taatttatac atctggaacc 780 actggtttgc ctaaatccgc tattatgtct tggagaaaat cctccgtagg ttgtcaagtt 840 tttggtcatg ttttacatat gactaatgaa agcactgtgt tcacagccat gccattgttc 900 cattcaactg ctgccttatt aggtgcgtgc gccattctat ctcacggtgg ttgccttgcg 960 ttatcgcata aattttctgc cagtacattt tggaagcaag tttatttaac aggagccacg 1020 cacatccaat atgtcggaga agtctgtaga tacctgttac atacgccaat ttctaagtat 1080 gaaaagatgc ataaggtgaa ggttgcttat ggtaacgggc tgagacctga catctggcag 1140 gacttcagga agaggttcaa catagaagtt attggtgaat tctatgccgc aactgaagct 1200 ccttttgcta caactacctt ccagaaaggt gactttggaa ttggcgcatg taggaactat 1260 ggtactataa ttcaatggtt tttgtcattc caacaaacat tggtaaggat ggacccaaat 1320 gacgattccg ttatatatag aaattccaag ggtttctgcg aagtggcccc tgttggcgaa 1380 ccaggagaaa tgttaatgag aatctttttc cctaaaaaac cagaaacatc ttttcaaggt 1440 tatcttggta atgccaagga aacaaagtcc aaagttgtga gggatgtctt cagacgtggc 1500 gatgcttggt atagatgtgg agatttatta aaagcggacg aatatggatt atggtatttc 1560 cttgatagaa tgggtgatac tttcagatgg aaatctgaaa atgtttccac tactgaagta 1620 gaagatcagt tgacggccag taacaaagaa caatatgcac aagttctagt tgttggtatt 1680 aaagtaccta aatatgaagg tagagctggt tttgcagtta ttaaactaac tgacaactct 1740 cttgacatca ctgcaaagac caaattatta aatgattcct tgagccggtt aaatctaccg 1800 tcttatgcta tgcccctatt tgttaaattt gttgatgaaa ttaaaatgac agataacctc 1860 ataaaatttt ga 1872 89 623 PRT Saccharomyces cerevisiae 89 Met Ser Pro Ile Gln Val Val Val Phe Ala Leu Ser Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu Ile Lys Leu Ile Ile Thr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe Gly Asn Tyr Phe Asp Glu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp Trp Tyr Ile Ile Pro Tyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile Asp Val Arg Arg His Arg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys Gln Val Gln Gln Asn Gly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro Met Ala Glu Lys Gly Glu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile Glu Thr Tyr Asn Ile Val Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe Asp Tyr Asn Val Gln Ala Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr Asn Lys Pro Leu Phe Val Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160 Gly Ala Ile Pro Ala Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170 175 Val His Ser Leu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180 185 190 Asp Ala Ser Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala 195 200 205 Leu Pro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu Met His 210 215 220 Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln Asp Asn Val 225 230 235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro Ser Met Leu Ile Tyr 245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser Trp Arg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val Leu His Met Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu Phe His Ser Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser His Gly Gly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe Ser Ala Ser Thr Phe Trp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr His Ile Gln Tyr Val Gly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr Pro Ile Ser Lys Tyr Glu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr Gly Asn Gly Leu Arg Pro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg Phe Asn Ile Glu Val Ile Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400 Pro Phe Ala Thr Thr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410 415 Cys Arg Asn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420 425 430 Thr Leu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn 435 440 445 Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly Glu Met 450 455 460 Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser Phe Gln Gly 465 470 475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val Arg Asp Val 485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu Leu Lys Ala 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly Asp Thr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val Glu Asp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val Leu Val Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr Glu Gly Arg Ala Gly Phe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser Leu Asp Ile Thr Ala Lys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser Arg Leu Asn Leu Pro Ser Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe Val Asp Glu Ile Lys Met Thr Asp Asn Leu Ile Lys Phe 610 615 620 90 1794 DNA Mycobacterium tuberculosis 90 gtgtccgatt actacggcgg cgcacacaca acggtcaggc tgatcgacct ggcaactcgg 60 atgccgcgag tgttggcgga cacgccggtg attgtgcgtg gggcaatgac cgggctgctg 120 gcccggccga attccaaggc gtcgatcggc acggtgttcc aggaccgggc cgctcgctac 180 ggtgaccgag tcttcctgaa attcggcgat cagcagctga cctaccgcga cgctaacgcc 240 accgccaacc ggtacgccgc ggtgttggcc gcccgcggcg tcggccccgg cgacgtcgtt 300 ggcatcatgt tgcgtaactc acccagcaca gtcttggcga tgctggccac ggtcaagtgc 360 ggcgctatcg ccggcatgct caactaccac cagcgcggcg aggtgttggc gcacagcctg 420 ggtctgctgg acgcgaaggt actgatcgca gagtccgact tggtcagcgc cgtcgccgaa 480 tgcggcgcct cgcgcggccg ggtagcgggc gacgtgctga ccgtcgagga cgtggagcga 540 ttcgccacaa cggcgcccgc caccaacccg gcgtcggcgt cggcggtgca agccaaagac 600 accgcgttct acatcttcac ctcgggcacc accggatttc ccaaggccag tgtcatgacg 660 catcatcggt ggctgcgggc gctggccgtc ttcggaggga tggggctgcg gctgaagggt 720 tccgacacgc tctacagctg cctgccgctg taccacaaca acgcgttaac ggtcgcggtg 780 tcgtcggtga tcaattctgg ggcgaccctg gcgctgggta agtcgttttc ggcgtcgcgg 840 ttctgggatg aggtgattgc caaccgggcg acggcgttcg tctacatcgg cgaaatctgc 900 cgttatctgc tcaaccagcc ggccaagccg accgaccgtg cccaccaggt gcgggtgatc 960 tgcggtaacg ggctgcggcc ggagatctgg gatgagttca ccacccgctt cggggtcgcg 1020 cgggtgtgcg agttctacgc cgccagcgaa ggcaactcgg cctttatcaa catcttcaac 1080 gtgcccagga ccgccggggt atcgccgatg ccgcttgcct ttgtggaata cgacctggac 1140 accggcgatc cgctgcggga tgcgagcggg cgagtgcgtc gggtacccga cggtgaaccc 1200 ggcctgttgc ttagccgggt caaccggctg cagccgttcg acggctacac cgacccggtt 1260 gccagcgaaa agaagttggt gcgcaacgct tttcgagatg gcgactgttg gttcaacacc 1320 ggtgacgtga tgagcccgca gggcatgggc catgccgcct tcgtcgatcg gctgggcgac 1380 accttccgct ggaagggcga gaatgtcgcc accactcagg tcgaagcggc actggcctcc 1440 gaccagaccg tcgaggagtg cacggtctac ggcgtccaga ttccgcgcac cggcgggcgc 1500 gccggaatgg ccgcgatcac actgcgcgct ggcgccgaat tcgacggcca ggcgctggcc 1560 cgaacggttt acggtcactt gcccggctat gcacttccgc tctttgttcg ggtagtgggg 1620 tcgctggcgc acaccacgac gttcaagagt cgcaaggtgg agttgcgcaa ccaggcctat 1680 ggcgccgaca tcgaggatcc gctgtacgta ctggccggcc cggacgaagg atatgtgccg 1740 tactacgccg aataccctga ggaggtttcg ctcggaaggc gaccgcaggg ctag 1794 91 597 PRT Mycobacterium tuberculosis 91 Met Ser Asp Tyr Tyr Gly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595 92 646 PRT Mus musculus 92 Met Arg Ala Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly Gly Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala Val Ala Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly Arg Tyr Leu Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 93 620 PRT Mus musculus VARIANT (1)...(620) Xaa = Any Amino Acid 93 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly Leu Leu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu Leu Gln Asp Val Arg Tyr 20 25 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg Val Arg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala Phe Leu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile Trp Leu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Ala Ser Pro Asp 145 150 155 160 Leu Gln Glu Ala Val Glu Glu Val Leu Pro Thr Leu Lys Lys Asp Ala 165 170 175 Val Ser Val Phe Tyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Ile Leu Asp Lys Val Asp Gly Val Ser Ala Glu Pro Thr Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Thr Ile Asn His His 225 230 235 240 Arg Leu Arg Tyr Gly Thr Gly Leu Ala Met Ser Ser Gly Ile Thr Ala 245 250 255 Gln Asp Val Ile Tyr Thr Thr Met Pro Leu Tyr His Ser Ala Ala Leu 260 265 270 Met Ile Gly Leu His Gly Cys Ile Val Val Gly Ala Xaa Xaa Xaa Leu 275 280 285 Cys Asp Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val Lys Lys Ala 325 330 335 Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Glu Phe Ile Lys Arg 340 345 350 Phe Gly Asp Ile His Val Tyr Glu Phe Tyr Ala Ser Thr Glu Gly Asn 355 360 365 Ile Gly Phe Val Asn Tyr Pro Arg Lys Ile Gly Ala Val Gly Arg Ala 370 375 380 Asn Tyr Leu Gln Arg Lys Val Ala Arg Tyr Glu Leu Ile Lys Tyr Asp 385 390 395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys 405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys Ile Thr Gln Leu 420 425 430 Thr Pro Phe Ile Gly Tyr Ala Gly Gly Lys Thr Gln Thr Glu Lys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Ile Tyr Phe Asn Ser Gly 450 455 460 Asp Leu Leu Met Ile Asp Arg Glu Asn Phe Val Tyr Phe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu Val Asn Val 500 505 510 Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly Met Ala Ser 515 520 525 Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr Phe Lys His Arg Lys Val 565 570 575 Thr Leu Met Glu Glu Gly Phe Asn Pro Thr Val Ile Lys Asp Thr Leu 580 585 590 Tyr Phe Met Asp Asp Ala Glu Lys Thr Phe Val Pro Met Thr Glu Asn 595 600 605 Ile Tyr Asn Ala Ile Ile Asp Lys Thr Leu Lys Leu 610 615 620 94 613 PRT Mus musculus 94 Ala Ala Asp Pro Glu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 Leu Ala Tyr Leu Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 Gly Ala Gln Arg Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 Ile Ala Arg Ala Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 Gly Ser Gly Arg Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80 Ala Gly Asp Ala Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95 Gly Ala Thr Val Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105 110 Ile Trp Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115 120 125 Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly 130 135 140 Ala Ser Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro 145 150 155 160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp Ala Thr Gly 165 170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala 180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro Gln Asn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His Leu Lys Val Leu Gln Cys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His Met Ser Gly Ser Leu Leu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly Ala Thr Val Val Leu Lys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp Asp Asp Cys Gln Lys His Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly Glu Leu Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 Glu Phe Asp His Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335 Asp Thr Trp Glu Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345 350 Glu Thr Tyr Gly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355 360 365 Gly Arg Gln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile 370 375 380 Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile 385 390 395 400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro Gly Glu Pro Gly 405 410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala 420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu Leu Lys Asp Val Phe Trp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp Arg Thr Gly Asp Thr Ile Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala Thr Thr Glu Val Ala Glu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln Glu Val Asn Ile Tyr Gly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg Ala Gly Met Ala Ala Leu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn Leu Val Gln Leu Tyr Ser His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 Thr Glu Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575 Asp Pro Ser Val Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585 590 Gly Ala Tyr Leu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595 600 605 Gly Asp Leu Arg Ile 610 95 506 PRT Mus musculus 95 His Ala Ser Ala His Ala Ser Gly Met Ala Lys Leu Gly Val Glu Ala 1 5 10 15 Ala Leu Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu 20 25 30 Asp Thr Ser Lys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser 35 40 45 Ala Ile Cys Glu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe 50 55 60 Cys Ser Gly Ser Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His 65 70 75 80 Leu Asp Pro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro 85 90 95 Asp Lys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110 Thr Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 115 120 125 Met Ala Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130 135 140 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly 145 150 155 160 Asp Trp Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys 165 170 175 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr 180 185 190 Val Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro 195 200 205 Pro Arg Glu Ala Glu Ser Arg His Lys Val Arg Met Ala Leu Gly Asn 210 215 220 Gly Leu Arg Gln Ser Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile 225 230 235 240 Pro Gln Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu 245 250 255 Gly Asn Phe Asp Ser Arg Val Gly Ala Cys Gly Phe Asn Ser Arg Ile 260 265 270 Leu Ser Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr 275 280 285 Met Glu Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro 290 295 300 Gly Gln Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu 305 310 315 320 Arg Arg Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 325 330 335 Ala Asn Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 340 345 350 Val Leu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360 365 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 370 375 380 Glu Gly Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr 385 390 395 400 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val 405 410 415 Ala Ser Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu 420 425 430 Lys Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu 435 440 445 Pro Glu Leu His Lys Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu 450 455 460 Arg Lys Glu Gly Phe Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr 465 470 475 480 Leu Asp Ala Arg Lys Gly Cys Tyr Val Ala Leu Asp Gln Glu Ala Tyr 485 490 495 Thr Arg Ile Gln Ala Gly Glu Glu Lys Leu 500 505 96 662 PRT Mus musculus 96 Met Ala Leu Ala Leu Arg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val 1 5 10 15 Leu Leu Gly Leu Ala Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met 20 25 30 Pro His Trp Leu Ser Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu 35 40 45 Pro Leu Gln Pro Pro Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala 50 55 60 Phe Thr Phe Lys Met Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu 65 70 75 80 Asn Lys His Pro Pro Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala 85 90 95 Leu Ala Trp Pro Asp Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly 100 105 110 Ser Ser Ile Thr Asn Ser Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala 115 120 125 Trp Val Leu Lys Ala Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg 130 135 140 Asp Ala Ala Ala Ile Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu 145 150 155 160 Ser Val Phe Leu Gly Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile 165 170 175 Asn Pro His Ser Arg Gly Met Pro Leu Leu His Ser Val Arg Ser Ser 180 185 190 Gly Ala Ser Val Leu Ile Val Asp Pro Asp Leu Gln Glu Asn Leu Glu 195 200 205 Glu Val Leu Pro Lys Leu Leu Ala Glu Asn Ile His Cys Phe Tyr Leu 210 215 220 Gly His Ser Ser Pro Thr Pro Gly Val Glu Ala Leu Gly Ala Ser Leu 225 230 235 240 Asp Ala Ala Pro Ser Asp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile 245 250 255 Lys Trp Lys Ser Pro Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly 260 265 270 Leu Pro Lys Pro Ala Ile Leu Ser His Glu Arg Val Ile Gln Val Ser 275 280 285 Asn Val Leu Ser Phe Cys Gly Cys Arg Ala Asp Asp Val Val Tyr Asp 290 295 300 Val Leu Pro Leu Tyr His Thr Ile Gly Leu Val Leu Gly Phe Leu Gly 305 310 315 320 Cys Leu Gln Val Gly Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala 325 330 335 Ser Arg Phe Trp Ala Glu Cys Arg Gln His Gly Val Thr Val Ile Leu 340 345 350 Tyr Val Gly Glu Ile Leu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro 355 360 365 Glu Asp Lys Ile His Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg 370 375 380 Ala Asn Val Trp Lys Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile 385 390 395 400 Trp Glu Phe Tyr Gly Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr 405 410 415 Val Gly His Cys Gly Ala Val Gly Arg Thr Ser Cys Ile Leu Arg Met 420 425 430 Leu Thr Pro Phe Glu Leu Val Gln Phe Asp Ile Glu Thr Ala Glu Pro 435 440 445 Leu Arg Asp Lys Gln Gly Phe Cys Ile Pro Val Glu Pro Gly Lys Pro 450 455 460 Gly Leu Leu Leu Thr Lys Val Arg Lys Asn Gln Pro Phe Leu Gly Tyr 465 470 475 480 Arg Gly Ser Gln Ala Glu Ser Asn Arg Lys Leu Val Ala Asn Val Arg 485 490 495 Arg Val Gly Asp Leu Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp 500 505 510 Gln Glu Gly Phe Phe Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg 515 520 525 Trp Lys Gly Glu Asn Val Ser Thr Gly Glu Val Glu Cys Val Leu Ser 530 535 540 Ser Leu Asp Phe Leu Glu Glu Val Asn Val Tyr Gly Val Pro Val Pro 545 550 555 560 Gly Cys Glu Gly Lys Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly 565 570 575 Lys Thr Phe Asp Gly Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu 580 585 590 Pro Ala Tyr Ala Thr Pro His Phe Ile Arg Ile Gln Asp Ser Leu Glu 595 600 605 Ile Thr Asn Thr Tyr Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly 610 615 620 Phe Asp Val Gly Ile Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys 625 630 635 640 Ala Gln Thr Phe Arg Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys 645 650 655 Glu Gly Thr Trp Asn Leu 660 97 650 PRT Caenorhabditis elegans 97 Met Lys Leu Glu Glu Leu Val Thr Val Met Leu Leu Thr Val Ala Val 1 5 10 15 Ile Ala Gln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly Val Leu Ile 20 25 30 Leu Tyr Ile Thr Val Val His Gly Asp Phe Ile Tyr Arg Ser Tyr Leu 35 40 45 Thr Leu Asn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile Glu Val Lys 50 55 60 Ile Asp Leu Trp Trp Arg Leu His Gln Asn Lys Gly Ile His Glu Leu 65 70 75 80 Phe Leu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro Ala Met Ile Asp 85 90 95 Ile Glu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe Asn Ala His Cys 100 105 110 Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly Tyr Arg Ser Gly Asp 115 120 125 Val Val Ala Leu Tyr Met Glu Asn Ser Val Glu Phe Val Ala Ala Trp 130 135 140 Met Gly Leu Ala Lys Ile Gly Val Val Thr Ala Trp Ile Asn Ser Asn 145 150 155 160 Leu Lys Arg Glu Gln Leu Val His Cys Ile Thr Ala Ser Lys Thr Lys 165 170 175 Ala Ile Ile Thr Ser Val Thr Leu Gln Asn Ile Met Leu Asp Ala Ile 180 185 190 Asp Gln Lys Leu Phe Asp Val Glu Gly Ile Glu Val Tyr Ser Val Gly 195 200 205 Glu Pro Lys Lys Asn Ser Gly Phe Lys Asn Leu Lys Lys Lys Leu Asp 210 215 220 Ala Gln Ile Thr Thr Glu Pro Lys Thr Leu Asp Ile Val Asp Phe Lys 225 230 235 240 Ser Ile Leu Cys Phe Ile Tyr Thr Ser Gly Thr Thr Gly Met Pro Lys 245 250 255 Ala Ala Val Met Lys His Phe Arg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270 Ala Lys Ser Phe Gly Ile Arg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280 285 Pro Ile Tyr His Thr Ala Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290 295 300 Leu Gly Gly Ser Ser Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn 305 310 315 320 Phe Trp Arg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser Gln Tyr Ile 325 330 335 Gly Glu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val Val Glu Glu Glu 340 345 350 Ser Arg His Arg Met Arg Leu Leu Val Gly Asn Gly Leu Arg Ala Glu 355 360 365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg Val Arg Ile Gly Glu Leu 370 375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser Leu Val Asn Ile Asp Gly His 385 390 395 400 Val Gly Ala Cys Gly Phe Leu Pro Ile Ser Pro Leu Thr Lys Lys Met 405 410 415 His Pro Val Arg Leu Ile Lys Val Asp Asp Val Thr Gly Glu Ala Ile 420 425 430 Arg Thr Ser Asp Gly Leu Cys Ile Ala Cys Asn Pro Gly Glu Ser Gly 435 440 445 Ala Met Val Ser Thr Ile Arg Lys Asn Asn Pro Leu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu Asn Lys Lys Glu Thr Asn Lys Lys Ile Ile Arg Asp Val 465 470 475 480 Phe Ala Lys Gly Asp Ser Cys Phe Leu Thr Gly Asp Leu Leu His Trp 485 490 495 Asp Arg Leu Gly Tyr Val Tyr Phe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510 Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520 525 His Pro Ile Thr Gly Leu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530 535 540 Pro Gln Arg Glu Gly Arg Val Gly Met Ala Ser Val Val Arg Val Val 545 550 555 560 Ser His Glu Glu Asp Glu Thr Gln Phe Val His Arg Val Gly Ala Arg 565 570 575 Leu Ala Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln Phe Met Arg Ile 580 585 590 Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys Leu Val Lys Thr Asn 595 600 605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro Ser Asp Ser Ile Tyr Ile 610 615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val Pro Phe Asp Asn Asp Leu Arg 625 630 635 640 Cys Lys Val Ser Leu Gly Ser Tyr Pro Phe 645 650 98 623 PRT Saccharomyces cerevisiae 98 Met Ser Pro Ile Gln Val Val Val Phe Ala Leu Ser Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu Ile Lys Leu Ile Ile Thr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe Gly Asn Tyr Phe Asp Glu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp Trp Tyr Ile Ile Pro Tyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile Asp Val Arg Arg His Arg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys Gln Val Gln Gln Asn Gly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro Met Ala Glu Lys Gly Glu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile Glu Thr Tyr Asn Ile Val Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe Asp Tyr Asn Val Gln Ala Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr Asn Lys Pro Leu Phe Val Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160 Gly Ala Ile Pro Ala Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170 175 Val His Ser Leu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180 185 190 Asp Ala Ser Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala 195 200 205 Leu Pro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu Met His 210 215 220 Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln Asp Asn Val 225 230 235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro Ser Met Leu Ile Tyr 245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser Trp Arg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val Leu His Met Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu Phe His Ser Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser His Gly Gly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe Ser Ala Ser Thr Phe Trp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr His Ile Gln Tyr Val Gly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr Pro Ile Ser Lys Tyr Glu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr Gly Asn Gly Leu Arg Pro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg Phe Asn Ile Glu Val Ile Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400 Pro Phe Ala Thr Thr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410 415 Cys Arg Asn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420 425 430 Thr Leu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn 435 440 445 Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly Glu Met 450 455 460 Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser Phe Gln Gly 465 470 475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val Arg Asp Val 485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu Leu Lys Ala 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly Asp Thr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val Glu Asp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val Leu Val Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr Glu Gly Arg Ala Gly Phe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser Leu Asp Ile Thr Ala Lys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser Arg Leu Asn Leu Pro Ser Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe Val Asp Glu Ile Lys Met Thr Asp Asn Leu Ile Lys Phe 610 615 620 99 597 PRT Mycobacterium tuberculosis 99 Met Ser Asp Tyr Tyr Gly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595 100 304 PRT concensus FATP signature sequence 100 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Ile Ile 1 5 10 15 Val His Ser Arg Tyr Tyr Arg Gly Ala Ala Leu His Ser Gly Arg Met 20 25 30 Arg Pro Asp Val Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ala Ala 35 40 45 Leu Ile Leu Gly Ile Gly Gln Cys Leu Leu His Gly Ala Thr Val Val 50 55 60 Leu Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Val Lys 65 70 75 80 Tyr Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu 85 90 95 Leu Asn Gln Pro Pro Arg Pro Ala Glu Arg Arg His Lys Val Arg Leu 100 105 110 Ala Val Gly Asn Gly Leu Arg Pro Asp Ile Trp Glu Glu Phe Val Ser 115 120 125 Arg Phe Gly Ile Pro Gln Ile Gly Glu Phe Tyr Gly Ala Thr Glu Gly 130 135 140 Asn Cys Ser Leu Met Asn Tyr Asp Gly Lys Val Gly Ala Cys Gly Ser 145 150 155 160 Arg Ile Leu Lys Lys Val Tyr Pro Ile Arg Leu Val Lys Val Asp Glu 165 170 175 Asp Thr Gly Glu Pro Ile Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys 180 185 190 Gln Pro Gly Glu Pro Gly Leu Leu Val Gly Arg Ile Asn Gln Gln Asp 195 200 205 Pro Phe Arg Gly Phe Gly Tyr Gly Ser Glu Gly Ala Thr Asn Lys Lys 210 215 220 Ile Ala Arg Asp Val Phe Lys Lys Gly Asp Val Ala Phe Asn Thr Gly 225 230 235 240 Asp Val Leu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg 245 250 255 Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu 260 265 270 Val Glu Gly Val Leu Ser Arg Leu Asp Phe Val Ala Glu Val Asn Val 275 280 285 Tyr Gly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met Ala Ala 290 295 300 101 2166 DNA Homo sapiens CDS (19)...(2124) 101 cgacccacgc gtccgggg atg ttt gcg agc ggc tgg aac cag acg gtg ccg 51 Met Phe Ala Ser Gly Trp Asn Gln Thr Val Pro 1 5 10 ata gag gaa gcg ggc tcc atg gct gcc ctc ctg ctg ctg ccc ctg ctg 99 Ile Glu Glu Ala Gly Ser Met Ala Ala Leu Leu Leu Leu Pro Leu Leu 15 20 25 ctg ttg cta ccg ctg ctg ctg ctg ctg aag cta cac ctc tgg ccg cag 147 Leu Leu Leu Pro Leu Leu Leu Leu Leu Lys Leu His Leu Trp Pro Gln 30 35 40 ttg cgc tgg ctt ccg gcg gac ttg gcc ttt gcg gtg cga gct ctg tgc 195 Leu Arg Trp Leu Pro Ala Asp Leu Ala Phe Ala Val Arg Ala Leu Cys 45 50 55 tgc aaa agg gct ctt cga gct cgc gcc ctg gcc gcg gct gcc gcc gac 243 Cys Lys Arg Ala Leu Arg Ala Arg Ala Leu Ala Ala Ala Ala Ala Asp 60 65 70 75 ccg gaa ggt ccc gag ggg ggc tgc agc ctg gcc tgg cgc ctc gcg gaa 291 Pro Glu Gly Pro Glu Gly Gly Cys Ser Leu Ala Trp Arg Leu Ala Glu 80 85 90 ctg gcc cag cag cgc gcc gcg cac acc ttt ctc att cac ggc tcg cgg 339 Leu Ala Gln Gln Arg Ala Ala His Thr Phe Leu Ile His Gly Ser Arg 95 100 105 cgc ttt agc tac tca gag gcg gag cgc gag agt aac agg gct gca cgc 387 Arg Phe Ser Tyr Ser Glu Ala Glu Arg Glu Ser Asn Arg Ala Ala Arg 110 115 120 gcc ttc cta cgt gcg cta ggc tgg gac tgg gga ccc gac ggc ggc gac 435 Ala Phe Leu Arg Ala Leu Gly Trp Asp Trp Gly Pro Asp Gly Gly Asp 125 130 135 agc ggc gag ggg agc gct gga gaa ggc gag cgg gca gcg ccg gga gcc 483 Ser Gly Glu Gly Ser Ala Gly Glu Gly Glu Arg Ala Ala Pro Gly Ala 140 145 150 155 gga gat gca gcg gcc gga agc ggc gcg gag ttt gcc gga ggg gac ggt 531 Gly Asp Ala Ala Ala Gly Ser Gly Ala Glu Phe Ala Gly Gly Asp Gly 160 165 170 gcc gcc aga ggt gga gga gag ccc gcc gcc cct ctg tca cct gga gca 579 Ala Ala Arg Gly Gly Gly Glu Pro Ala Ala Pro Leu Ser Pro Gly Ala 175 180 185 act gtg gcg ctg ctc ctc ccc gct ggc cca gag ttt ctg tgg ctc tgg 627 Thr Val Ala Leu Leu Leu Pro Ala Gly Pro Glu Phe Leu Trp Leu Trp 190 195 200 ttc ggg ctg gcc aag gcc ggc ctg cgc act gcc ttt gtg ccc acc gcc 675 Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala 205 210 215 ctg cgc cgg ggc ccc ctg ctg cac tgc ctc cgc agc tgc ggc gcg cgc 723 Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly Ala Arg 220 225 230 235 gcg ctg gtg ctg gcg cca gag ttt ctg gag tcc ctg gag ccg gac ctg 771 Ala Leu Val Leu Ala Pro Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu 240 245 250 ccc gcc ctg aga gcc atg ggg ctc cac ctg tgg gct gca ggc cca gga 819 Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp Ala Ala Gly Pro Gly 255 260 265 acc cac cct gct gga att agc gat ttg ctg gct gaa gtg tcc gct gaa 867 Thr His Pro Ala Gly Ile Ser Asp Leu Leu Ala Glu Val Ser Ala Glu 270 275 280 gtg gat ggg cca gtg cca gga tac ctc tct tcc ccc cag agc ata aca 915 Val Asp Gly Pro Val Pro Gly Tyr Leu Ser Ser Pro Gln Ser Ile Thr 285 290 295 gac acg tgc ctg tac atc ttc acc tct ggc acc acg ggc ctc ccc aag 963 Asp Thr Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys 300 305 310 315 gct gct cgg atc agt cat ctg aag atc ctg caa tgc cag ggc ttc tat 1011 Ala Ala Arg Ile Ser His Leu Lys Ile Leu Gln Cys Gln Gly Phe Tyr 320 325 330 cag ctg tgt ggt gtc cac cag gaa gat gtg atc tac ctc gcc ctc cca 1059 Gln Leu Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala Leu Pro 335 340 345 ctc tac cac atg tcc ggt tcc ctg ctg ggc atc gtg ggc tgc atg ggc 1107 Leu Tyr His Met Ser Gly Ser Leu Leu Gly Ile Val Gly Cys Met Gly 350 355 360 att ggg gcc aca gtg gtg ctg aaa tcc aag ttc tcg gct ggt cag ttc 1155 Ile Gly Ala Thr Val Val Leu Lys Ser Lys Phe Ser Ala Gly Gln Phe 365 370 375 tgg gaa gat tgc cag cag cac agg gtg acg gtg ttc cag tac att ggg 1203 Trp Glu Asp Cys Gln Gln His Arg Val Thr Val Phe Gln Tyr Ile Gly 380 385 390 395 gag ctg tgc cga tac ctt gtc aac cag ccc ccg agc aag gca gaa cgt 1251 Glu Leu Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg 400 405 410 ggc cat aag gtc cgg ctg gca gtg ggc agc ggg ctg cgc cca gat acc 1299 Gly His Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr 415 420 425 tgg gag cgt ttt gtg cgg cgc ttc ggg ccc ctg cag gtg ctg gag aca 1347 Trp Glu Arg Phe Val Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr 430 435 440 tat gga ctg aca gag ggc aac gtg gcc acc atc aac tac aca gga cag 1395 Tyr Gly Leu Thr Glu Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln 445 450 455 cgg ggc gct gtg ggg cgt gct tcc tgg ctt tac aag cat atc ttc ccc 1443 Arg Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro 460 465 470 475 ttc tcc ttg att cgc tat gat gtc acc aca gga gag cca att cgg gac 1491 Phe Ser Leu Ile Arg Tyr Asp Val Thr Thr Gly Glu Pro Ile Arg Asp 480 485 490 ccc cag ggg cac tgt atg gcc aca tct cca ggt gag cca ggg ctg ctg 1539 Pro Gln Gly His Cys Met Ala Thr Ser Pro Gly Glu Pro Gly Leu Leu 495 500 505 gtg gcc ccg gta agc cag cag tcc cca ttc ctg ggc tat gct ggc ggg 1587 Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Gly 510 515 520 cca gag ctg gcc cag ggg aag ttg cta aag gat gtc ttc cgg cct ggg 1635 Pro Glu Leu Ala Gln Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly 525 530 535 gat gtt ttc ttc aac act ggg gac ctg ctg gtc tgc gat gac caa ggt 1683 Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly 540 545 550 555 ttt ctc cgc ttc cat gat cgt act gga gac acc ttc agg tgg aag ggg 1731 Phe Leu Arg Phe His Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly 560 565 570 gag aat gtg gcc aca acc gag gtg gca gag gtc ttc gag gcc cta gat 1779 Glu Asn Val Ala Thr Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp 575 580 585 ttt ctt cag gag gtg aac gtc tat gga gtc act gtg cca ggg cat gaa 1827 Phe Leu Gln Glu Val Asn Val Tyr Gly Val Thr Val Pro Gly His Glu 590 595 600 ggc agg gct gga atg gca gcc cta gtt ctg cgt ccc ccc cac gct ttg 1875 Gly Arg Ala Gly Met Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu 605 610 615 gac ctt atg cag ctc tac acc cac gtg tct gag aac ttg cca cct tat 1923 Asp Leu Met Gln Leu Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr 620 625 630 635 gcc cgg ccc cga ttc ctc agg ctc cag gag tct ttg gcc acc aca gag 1971 Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu 640 645 650 acc ttc aaa cag cag aaa gtt cgg atg gca aat gag ggc ttc gac ccc 2019 Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro 655 660 665 agc acc ctg tct gac cca ctg tac gtt ctg gac cag gct gta ggt gcc 2067 Ser Thr Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala 670 675 680 tac ctg ccc ctc aca act gcc cgg tac agc gcc ctc ctg gca gga aac 2115 Tyr Leu Pro Leu Thr Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn 685 690 695 ctt cga atc tgagaacttc cacacctgag gcacctgaga gaggaactct 2164 Leu Arg Ile 700 gt 2166 102 702 PRT Homo sapiens 102 Met Phe Ala Ser Gly Trp Asn Gln Thr Val Pro Ile Glu Glu Ala Gly 1 5 10 15 Ser Met Ala Ala Leu Leu Leu Leu Pro Leu Leu Leu Leu Leu Pro Leu 20 25 30 Leu Leu Leu Leu Lys Leu His Leu Trp Pro Gln Leu Arg Trp Leu Pro 35 40 45 Ala Asp Leu Ala Phe Ala Val Arg Ala Leu Cys Cys Lys Arg Ala Leu 50 55 60 Arg Ala Arg Ala Leu Ala Ala Ala Ala Ala Asp Pro Glu Gly Pro Glu 65 70 75 80 Gly Gly Cys Ser Leu Ala Trp Arg Leu Ala Glu Leu Ala Gln Gln Arg 85 90 95 Ala Ala His Thr Phe Leu Ile His Gly Ser Arg Arg Phe Ser Tyr Ser 100 105 110 Glu Ala Glu Arg Glu Ser Asn Arg Ala Ala Arg Ala Phe Leu Arg Ala 115 120 125 Leu Gly Trp Asp Trp Gly Pro Asp Gly Gly Asp Ser Gly Glu Gly Ser 130 135 140 Ala Gly Glu Gly Glu Arg Ala Ala Pro Gly Ala Gly Asp Ala Ala Ala 145 150 155 160 Gly Ser Gly Ala Glu Phe Ala Gly Gly Asp Gly Ala Ala Arg Gly Gly 165 170 175 Gly Glu Pro Ala Ala Pro Leu Ser Pro Gly Ala Thr Val Ala Leu Leu 180 185 190 Leu Pro Ala Gly Pro Glu Phe Leu Trp Leu Trp Phe Gly Leu Ala Lys 195 200 205 Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala Leu Arg Arg Gly Pro 210 215 220 Leu Leu His Cys Leu Arg Ser Cys Gly Ala Arg Ala Leu Val Leu Ala 225 230 235 240 Pro Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu Pro Ala Leu Arg Ala 245 250 255 Met Gly Leu His Leu Trp Ala Ala Gly Pro Gly Thr His Pro Ala Gly 260 265 270 Ile Ser Asp Leu Leu Ala Glu Val Ser Ala Glu Val Asp Gly Pro Val 275 280 285 Pro Gly Tyr Leu Ser Ser Pro Gln Ser Ile Thr Asp Thr Cys Leu Tyr 290 295 300 Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Arg Ile Ser 305 310 315 320 His Leu Lys Ile Leu Gln Cys Gln Gly Phe Tyr Gln Leu Cys Gly Val 325 330 335 His Gln Glu Asp Val Ile Tyr Leu Ala Leu Pro Leu Tyr His Met Ser 340 345 350 Gly Ser Leu Leu Gly Ile Val Gly Cys Met Gly Ile Gly Ala Thr Val 355 360 365 Val Leu Lys Ser Lys Phe Ser Ala Gly Gln Phe Trp Glu Asp Cys Gln 370 375 380 Gln His Arg Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr 385 390 395 400 Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg Gly His Lys Val Arg 405 410 415 Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr Trp Glu Arg Phe Val 420 425 430 Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr Tyr Gly Leu Thr Glu 435 440 445 Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln Arg Gly Ala Val Gly 450 455 460 Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro Phe Ser Leu Ile Arg 465 470 475 480 Tyr Asp Val Thr Thr Gly Glu Pro Ile Arg Asp Pro Gln Gly His Cys 485 490 495 Met Ala Thr Ser Pro Gly Glu Pro Gly Leu Leu Val Ala Pro Val Ser 500 505 510 Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Gly Pro Glu Leu Ala Gln 515 520 525 Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly Asp Val Phe Phe Asn 530 535 540 Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly Phe Leu Arg Phe His 545 550 555 560 Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr 565 570 575 Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu Val 580 585 590 Asn Val Tyr Gly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met 595 600 605 Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln Leu 610 615 620 Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe 625 630 635 640 Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln 645 650 655 Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser Asp 660 665 670 Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro Leu Thr 675 680 685 Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile 690 695 700 103 19 DNA Artificial Sequence Oligonucleotide 103 cccccaccag agaggctcc 19 104 19 DNA Artificial Sequence Oligonucleotide 104 ccacccccgg aaagcctgc 19 105 19 DNA Artificial Sequence Oligonucleotide 105 ggagcctctc tggtggggg 19 

What is claimed is:
 1. An isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 24 or SEQ ID NO: 46 or the complement thereof.
 2. An isolated nucleic acid which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 25 or the complement thereof.
 3. An isolated nucleic acid which hybridizes under stringency conditions 6×SSC at 650° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C. to a nucleic acid comprising the nucleotide sequence of SEQ ID NO; 24 or SEQ ID NO: 46 or the complement thereof.
 4. An isolated nucleic acid consisting of the nucleotide sequence of SEQ ID NO: 24 or SEQ ID NO: 46 or the complement thereof.
 5. An isolated nucleic acid which encodes a polypeptide consisting of the amino acid sequence of SEQ. ID NO: 25 or the complement thereof.
 6. An isolated nucleic acid comprising the nucleotide sequence of the coding region of SEQ ID NO: 24 or SEQ ID NO:
 46. 7. An isolated nucleic acid comprising a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO; 24 or SEQ ID NO:
 46. 8. An isolated nucleic acid encoding a fusion polypeptide, wherein the isolated nucleic acid comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
 25. 9. An isolated nucleic acid comprising at least 1080 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 24 or SEQ ID NO: 46 or a complement thereof.
 10. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 360 amino acids of the sequence or SEQ ID NO: 25 or a complement thereof.
 11. A vector comprising a nucleic acid of any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or
 10. 12. An isolated host cell transfected with the vector of claim
 11. 13. A method for producing a polypeptide comprising the step of culturing the host cell of claim 12 under conditions in which the nucleic acid is expressed, thereby producing the polypeptide.
 14. An isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 101 or the complement thereof.
 15. An isolated nucleic acid which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 102 or the complement thereof.
 16. An isolated nucleic acid which hybridizes under stringency conditions of 6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C. to a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 101 or the complement thereof.
 17. An isolated nucleic acid consisting of the nucleotide sequence of SEQ ID NO: 101 or the complement thereof.
 18. An isolated nucleic acid which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO: 102 or the complement thereof.
 19. An isolated nucleic acid comprising the nucleotide sequence of the coding region of SEQ ID NO:
 101. 20. An isolated nucleic acid comprising a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO:
 101. 21. An isolated nucleic acid encoding a fusion polypeptide, wherein the isolated nucleic acid comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
 102. 22. An isolated nucleic acid comprising at least 1080 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 101 or a complement thereof.
 23. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 360 amino acids of the sequence of SEQ ID NO: 102 or a complement thereof.
 24. An isolated nucleic acid comprising at least 30 contiguous nucleotides of the nucleotide sequence of SEQ ID NO:
 101. 25. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 15 amino acids of the sequence of SEQ ID NO:
 102. 26. A vector comprising a nucleic acid of any one of claims 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or
 25. 27. An isolated host cell transfected with the vector of claim
 26. 28. A method for producing a polypeptide comprising the step of culturing the host cell of claim 27 under conditions in which the nucleic acid is expressed, thereby producing the polypeptide.
 29. An isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 26 or SEQ ID NO: 52 or the complement thereof.
 30. An isolated nucleic acid which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 27 or the complement thereof.
 31. An isolated nucleic acid which hybridizes under stringency conditions of 6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C. to a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 26 or SEQ ID NO: 52 or the complement thereof.
 32. An isolated nucleic acid consisting of the nucleotide sequence of SEQ ID NO: 26 or SEQ ID NO; 52 or the complement thereof.
 33. An isolated nucleic acid which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO: 27 or the complement thereof.
 34. An isolated nucleic acid comprising the nucleotide sequence of the coding region of SEQ ID NO: 26 or SEQ ID NO:
 52. 35. An isolated nucleic acid comprising a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO: 26 or SEQ ID NO:
 52. 36. An isolated nucleic acid encoding a fusion polypeptide, wherein the isolated nucleic acid comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO.
 27. 37. An isolated nucleic acid comprising at least 1080 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 26 or SEQ ID NO: 52 or a complement thereof.
 38. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 360 amino acids of the sequence of SEQ ID NO: 27 or a complement thereof.
 39. A vector comprising a nucleic acid of any one of claims 29, 30, 31, 32, 33, 34, 35, 36, 37, or
 38. 40. An isolated host cell transfected with the vector of claim
 39. 41. A method for producing a polypeptide comprising the step of culturing the host cell of claim 40 under conditions in which the nucleic acid is expressed, thereby producing the polypeptide.
 42. An isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 54 or the complement thereof.
 43. An isolated nucleic acid which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 55 or the complement thereof.
 44. An isolated nucleic acid consisting of the nucleotide sequence of SEQ ID NO: 54 or the complement thereof.
 45. An isolated nucleic acid which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO: 55 or the complement thereof.
 46. An isolated nucleic acid comprising the nucleotide sequence of the coding region of SEQ ID NO:
 54. 47. An isolated nucleic acid encoding a fusion polypeptide, wherein the isolated nucleic acid comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
 55. 48. An isolated nucleic acid comprising at least 1080 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 54 or a complement thereof.
 49. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 360 amino acids of the sequence of SEQ ID NO: 55 or a complement thereof.
 50. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 15 amino acids of the sequence of SEQ ID NO:
 55. 51. A vector comprising a nucleic acid of any one of claims 42, 43, 44, 45, 46, 47, 48, 49 or
 50. 52. An isolated host cell transfected with the vector of claim
 51. 53. A method for producing a polypeptide comprising the step of culturing the host cell of claim 52 under conditions in which the nucleic acid is expressed, thereby producing the polypeptide.
 54. An isolated nucleic acid comprising the nucleotide sequence of SEQ ID NO: 56 or the complement thereof.
 55. An isolated nucleic acid which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 57 or the complement thereof.
 56. An isolated nucleic acid which hybridizes under stringency conditions of 6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C. to a nucleic acid comprising the full coding region of the nucleotide sequence of SEQ ID NO: 56 or the complement thereof.
 57. An isolated nucleic acid consisting of the nucleotide sequence of SEQ ID NO: 56 or the complement thereof.
 58. An isolated nucleic acid which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO: 57 or the complement thereof.
 59. An isolated nucleic acid comprising the nucleotide sequence of the coding region of SEQ ID NO:
 56. 60. An isolated nucleic acid comprising a nucleotide sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO:
 56. 61. An isolated nucleic acid encoding a fusion polypeptide, wherein the isolated nucleic acid comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:
 57. 62. An isolated nucleic acid comprising at least 1080 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 56 or a complement thereof.
 63. An isolated nucleic acid comprising a nucleotide sequence which encodes a contiguous portion of at least 360 amino acids of the sequence of SEQ ID NO: 57 or a complement thereof.
 64. A vector comprising a nucleic acid of any one of claims 54, 55, 56, 57, 58, 59, 60, 61, 62 or
 63. 65. An isolated host cell transfected with the vector of claim
 64. 66. A method for producing a polypeptide comprising the step of culturing the host cell of claim 65 under conditions in which the nucleic acid is expressed, thereby producing the polypeptide. 